BRPI0714886A2 - fast-acting benzodiazepine salts and their polymorphic forms - Google Patents

Abstract

QUICK ACTION BENZODIAZEPIN SALTS AND THEIR POLYMORPHIC FORMS. The present invention relates to besylate salts of the compound of formula (1): Methods for preparing the salts and their use as medicaments are also described, in particular for sedative or hypnotic, anxiolytic, muscle relaxant or anticonvulsant purposes.

Description

Report of the Invention Patent for "FAST ACTION BENZODIAZEPIN SALTS AND THEIR POLYMORPHIC FORMS".

The present invention relates to fast acting benzodiazepine salts and the use of salts as medicaments, in particular for sedative or hypnotic, anxiolytic, muscle relaxant or anticonvulsant purposes.

European Patent No. No. 1,183,243 describes fast acting benzodiazepines which include a carboxylic acid ester group and are inactivated by specific nonwoven esterases. An organ-independent elimination mechanism is predicted to be characteristic of these benzodiazepines, providing a predictable and reproducible pharmacodynamic profile. The compounds are suitable for therapeutic purposes, including for sedative purposes - hypnotic, anxiolytic, muscle relaxants and anticonvulsants. The compounds are fast acting CNS depressants that are useful for intravenous administration in the following clinical situations: preoperative sedation, anxiolysis and domestic use for perioperative events; conscious sedation during brief diagnostic, operative or endoscopic procedures; as a component for the induction and maintenance of general anesthesia prior to and / or concomitant with the administration of other anesthetic or analgesic agents; ICU sedation.

One of the compounds described in EP 1,183,243 (in Example 1c-8, page 36) is 3 - [(4S) -8-bromo-1-methyl-6- (2-pyridinyl) -4H-imidazole Methyl [1,2-a] [1,4] benzodiazepin-4-yl] propanoate as given in formula (I) below: CO2CH3 (I)

Although the free base of formula (I) is stable when stored at 5 ° C, it is observed that samples stored at 40 ° C / 75% relative (open) humidity become yellow in color. orange and have noticeable decreases in grade from the initial (see Example 1 below).

It has surprisingly been found that the compound of formula (I) forms highly crystalline besylate (benzenesulfonic acid) mono salts which are easily isolated from a range of pharmaceutically acceptable solvents and exhibit good thermal stability, low hygroscopicity and high aqueous solubility.

According to the invention there is provided the besylate salt of a compound of formula (I). Preferably the salt is a crystalline salt. Preferably the crystalline salt has a 1: 1 stoichiometry of compound of formula (1): besylate. The preparation and characterization of polymorphic forms of besylate salts are described in the following Examples.

According to the invention there is provided a crystalline besylate salt polymorph of a compound of formula (I) (herein designated besylate Form 1), which exhibits an X-ray diffraction pattern (XRPD) comprising a characteristic peak at around 7.3, 7.8, 9.4, 12.1, 14.1, 14.4, 14.7 or 15.6 degrees two theta. Preferably the besylate Form 1 crystalline polymorph exhibits an XRPD pattern comprising characteristic peaks around 7.3, 7.8, 9.4, 12.1, 14.1, 14.4, 14, 7, and 15.6 degrees two theta.

More preferably the crystalline Formylate beetle polymorph exhibits an XRPD pattern comprising characteristic peaks at: 7.25 (10.60), 7.84 (72.60), 9.36 (12.10), 12.13 (32.50), 14.06 (48.50), 14.41 (74.30), 14.70 (50.70), 15.60 (26.90) degrees two theta angle ( percentage of relative intensity).

Preferably the besylate Form 1 crystalline polymorph has a differential scanning calorimetry (DSC) onset melting temperature in the range of 187-204 ° C, preferably around 191-192 ° C.

A crystal structure of Form 1 was resolved at 190 K (R factor of 6.3). Form I has a 1: 1 stoichiometry of compound: besylate. Its asymmetric crystallographic unit contains two independent compound molecules and two besylate molecules. The two independent compound molecules are isolated alone on the imidazole ring. The crystal structure has unit cell dimensions of a = 7,6868 A, b = 29,2607 A, c = 12,3756 A, α = 90 °, β = 97,7880 °, γ = 90 ° and a group P2 space. The crystal structure is described in more detail in Example 9 and the crystallographic coordinates are given in Table 17. The bond lengths and angles for Form 1 are given in Tables 19 and 20, respectively.

According to the invention there is provided the besylate salt of a compound of formula (I) which is a crystalline polymorph comprising a crystal with unit cell dimensions of a = 7.6868 A, b = 29.2607 A, c = 12 , 3756 A1 α - 90 °, β = 97.7880 °, γ = 90 °.

Also provided according to the invention is the besylate salt of a compound of formula (I) which is a crystalline polymorph having a crystal structure defined by the structural coordinates as shown in Table 17.

Also provided according to the invention is the besylate salt of a compound of formula (I) with binding lengths and angles as shown in Tables 19 and 20, respectively.

Also provided according to the invention is a besylate crystalline salt polymorph of a compound of formula (I) (hereinafter Form 2 benzylate), which exhibits an XRPD pattern comprising a characteristic peak of about 8.6, 10.5, 12.0, 13.1, 14.4 or 15.9 degrees two theta.

Preferably the besylate crystalline polymorph Form 2 exhibits an XRPD pattern comprising characteristic peaks around 8.6, 10.5, 12.0, 13.1, 14.4 and 15.9 degrees two theta.

More preferably the Form 2 crystalline besylate polymorph exhibits an XRPD pattern comprising characteristic peaks at: 8.64 (17.60), 10.46 (21.00), 12.03 (22.80), 13, 14 (27.70), 14.42 (11.20), 15.91 (100.00) angle two theta degrees (percentage of relative intensity).

Preferably, the Form 2 crystalline besylate polymorph has a differential scanning calorimetry (DSC) melt initiation temperature in the range of 170-200 ° C, preferably around 180 ° C.

A Form 2 crystal structure was resolved at 190 K (R factor 3.8). Form 2 has a 1: 1 compound: besylate stoichiometry. Its asymmetric crystallographic unit contains one compound molecule and one besylate molecule. The compound molecule is protonated alone over the imidazole ring. The crystal structure has single cell dimensions of a = 8.92130 A, b = 11.1536 A, c = 25.8345 A, α = 90 °, β = 90 °, γ = 90 ° and a group P21212i spacecraft. The crystal structure is described in more detail in Example 10 and the crystallographic coordinates are given in Table 18. The bond lengths and angles for Form 2 are given in Tables 21 and 22, respectively.

According to the invention there is provided besylate salt of a compound of formula (I) which is a crystalline polymorph comprising a crystal with unit cell dimensions of a = 8.92130 A, b = 11.1536 A1 c = 25.8345 A, α = 90 °, β = 90 °, γ = 90 °. Also provided according to the invention is besylate salt of

a compound of formula (I) which is a crystalline polymorph which has a crystal structure defined by the structural coordinates as shown in Table 18.

Also provided according to the invention is the besylate salt of a compound of formula (I) with binding lengths and angles as shown in Tables 21 and 22, respectively.

Also provided according to the invention is a polymorph

crystallization of the besylate salt of a compound of formula (I) (herein designated Form 3 benzylate), which exhibits an X-ray diffraction pattern (XRPD) comprising a characteristic peak of around 7.6, 11.2, 12.4, 14.6, 15.2, 16.4 or 17.7 degrees two theta. Preferably the besylate Form 3 crystalline polymorph exhibits a

XRPD standard comprising characteristic peaks around: 7.6, 11.2, 12.4, 14.6, 15.2, 16.4, and 17.7 degrees two theta.

More preferably the Form 3 crystalline besylate polymorph exhibits an XRPD pattern comprising characteristic peaks at: 7.61 (65.70), 11.19 (33.20), 12.38 (48.70), 14, 63 (30.60), 15.18 (33.20), 16.40 (29.60), 17.68 (51.30) angle 20 ° (percent relative intensity).

Preferably the Form 3 crystalline besylate polymorph has a differential scanning calorimetry (DSC) melting initiation temperature in the range of 195-205 ° C, preferably around 200-201 ° C. Also provided according to the invention is a polymorph

crystalline besylate salt of a compound of formula (I) (herein designated Form 4 benzylate), which exhibits an XRPD pattern comprising a characteristic peak of around 7.6, 10.8, 15.2, 15, 9 or 22.0 degrees two theta.

Preferably the besylate Form 4 crystalline polymorph exhibits an XRPD pattern comprising characteristic peaks around: 7.6, 10.8, 15.2, 15.9, and 22.0 degrees two theta.

Preferably the besylate Form 4 crystalline polymorph exhibits an XRPD pattern comprising characteristic peaks at: 7.62 (83.50), 10.75 (14.70), 15.17 (37.80), 15.85 ( 28.70), 22.03 (100) angle 20 ° (relative intensity percentage).

Preferably the Besylate Form 4 crystalline polymorph has the differential scanning calorimetry (DSC) onset melting temperature in the range of 180-185 ° C, preferably around 182 ° C.

A preferred salt is Form 1 besylate based on robustness of formation, yield, purity and chemical stability and solid form.

Also provided according to the invention is a process for obtaining a besylate salt of a compound of formula (I) comprising reacting a free base of a compound of formula (I) with benzene sulfonic acid.

Also according to the invention there is provided a process for obtaining a salt of the invention comprising contacting a free base of a compound of formula (I) with benzene sulfonic acid in solution to cause a precipitate to form. besylate salt. Preferably the process also comprises isolating the precipitate.

Preferably the free base is dissolved in toluene, ethanol, ethyl acetate, MtBE, dichloromethane (DCM), isopropyl acetate, ethyl formate, methanol or acetone. More preferably the free base is dissolved in toluene or ethyl acetate. Preferably the benzene sulfonic acid is dissolved in ethanol.

Form 1 besylate may be prepared by contacting a free base solution of a compound of formula (I) in toluene, ethyl acetate, acetone, isopropyl acetate or ethyl formate with a solution of benzene sulfonic acid in ethanol to cause a salt precipitate to form.

Also provided according to the invention is the besylate salt of a compound of formula (I) which may be obtained by the above process. Besylate Form 2 be prepared by contacting a solution

of a free base of a compound of formula (I) in methanol with a solution of benzene sulfonic acid in ethanol to cause a salt precipitate to form. Preferably the mixture is cooled to below room temperature (e.g. 4 ° C). Also provided according to the invention is the besylate salt of

a compound of formula (I) which is may be obtained by the above process.

Form 3 besylate can be prepared by seeding solution resulting from the crystallization of Form 1 from ethyl acetate / ethanol to Form 1. Preferably, the solution is cooled to below room temperature (e.g. 4 ° C).

In one embodiment, Form 3 besylate may be prepared by separating, with a Form 1 crystalline besylate salt of a compound of formula (I), a solution of the filtrate separated from the precipitate formed by contacting a solution of a compound of formula (I). ) in ethyl acetate with a solution of benzenesulfonic acid in ethanol to produce crystalline polymorph besylate Form 3. Also provided according to the invention is besylate salt of

a compound of formula (I) obtainable by the above processes.

Form 4 besylate may be prepared by recrystallization of Form 1 besylate starting from isopropyl acetate / ethanol, preferably 40% isopropyl acetate / ethanol. Also provided according to the invention is the besylate salt of

a compound of formula (I) obtainable by the above process.

Salts of the invention may also be prepared by crystallizing the compound of formula (I) besylate from a suitable solvent or a suitable solvent / antisolvent or solvent / cosolvent mixture. The solution or mixture may be cooled and / or evaporated to achieve crystallization if appropriate.

Crystallization of Form 2 has been found to be observed under conditions where there are extremes of polarity (eg acetonitrile: water) or lipophilicity (n-nonane) or both (dimethyl sulfoxide: 1,2-dichlorobenzene).

Examples of solvents for crystallization of Form 2 are: nanane; methanol.

Examples of solvent / antisolvent mixtures for the crystallization of Form 1 are: dimethylacetamide / methyl isobutyl ketone; dimethylacetamide / tetrachlorethylene; acetonitrile / 3-methylbutan-1-ol; acetonitrile / 1,2-dichlorobenzene; acetonitrile / pentyl acetate; methanol / 3-methylbutan-1-ol; methanol / methyl isobutyl ketone; 2,2,2-trifluoro ethanol / 1,4-dimethylbenzene; ethanolol / methyl isobutyl ketone; ethanol / 1,4-dimethylbenzene; propan-1-ol / 1,2-dichlorobenzene; propan-1-ol / tetrachlorethylene; propan-2-ol / 1,2-dichlorobenzene; propan-2-ol / n-nonane; 2-methoxy ethanol / water; 2-methoxy ethanol / pentyl acetate; 2-methoxy ethanol / 1,4-dimethylbenzene; tetrahydrofuran / water; tetrahydrofuran / 3-methylbutan-1-ol; tetrahydrofuran / 1,2-dichlorobenzene; tetrahydrofuran / ethyl acetate; tetrahydrofuran / 1,3-dimethylbenzene.

Examples of solvent / antisolvent mixtures for crystallization of Form 2 are: ethanol / ethyl acetate; ethanol / methyl isobutyl ketone; ethanol / p-cymene; dimethyl sulfoxide / 1,2-dichlorobenzene; acetonitrile / water; ethane / 1,2-dichlorobenzene; ethanol / tetrachlorethylene; tetrahydrofuran / 1,2-dichlorobenzene; tetrahydrofuran / ethyl acetate.

According to a preferred embodiment, Form 1 is crystallized from 2-methoxyethanol / pentyl acetate. According to a preferred embodiment, Form 2 is crystallized.

ethanol / ethyl acetate.

According to a preferred embodiment, Form 2 is crystallized from methanol / ethanol (preferably by cooling a solution of the compound of formula (I) besylate in methanol / ethanol to below room temperature, e.g. ° C).

According to a preferred embodiment, Form 3 is crystallized from ethanol / ethyl acetate (suitably by cooling the mixture to below room temperature, for example 4 ° C).

According to a preferred embodiment, Form 4 is crystallized from isopropyl acetate / ethanol (preferably by cooling a solution of the compound of formula (I) besylate in isopropyl acetate / ethanol to room temperature).

Also provided according to the invention is the besylate salt of a compound of formula (I) obtainable by any of the above processes.

The salt preparation processes of the invention are described in detail in the following Examples. The salt of the invention may be used as a medicament, in particular for sedative or hypnotic, anxiolytic, muscle relaxant or anticonvulsant purposes.

While it is possible for the salt of the invention to be administered as a bulky active substance, it is preferably provided with a pharmaceutically acceptable carrier, excipient or diluent in the form of a pharmaceutical composition. The vehicle, excipient or diluent must, of course, be acceptable in the sense that it is compatible with the other ingredients of the composition and must not be harmful to the container. Accordingly, the present invention provides a composition

A pharmaceutical composition comprising a salt of the invention and a pharmaceutically acceptable carrier, excipient or diluent.

Pharmaceutical compositions of the invention include those suitable for oral, rectal, topical, buccal (e.g. sublingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration.

Preferably, the salt of the invention is provided as a pharmaceutical composition for parenteral administration, for example by intravenous or intramuscular injection of a solution. Where the pharmaceutical composition is for parenteral administration, a composition may be an aqueous or non-aqueous solution or a mixture of liquids, which may include bacteriostatic agents, antioxidants, drums or other pharmaceutically acceptable additives.

A preferred formulation of a salt of the invention is an acidic aqueous medium of pH 2-4 or an aqueous solution of a cyclodextrin (CD). The cyclodextrins that may be used for these formulations are the anionically charged β-CD sulfobutyl ether (SBE) derivatives, specifically SBE7-P-CD, sold under the tradename Captisol by CyDex, Inc. (Critical Reviews in Therapeutic Drug Carrier Systems, 14 (1), 1-104 (1997)) or the hydroxypropyl CD's.

Another preferred salt formulation of the invention is a lyophilized formulation which comprises, in addition to the salt, at least one of the following agents: ascorbic acid, citric acid, maleic acid, phosphoric acid, glycine, glycine hydrochloride, succinic acid or tartaric acid. These agents are believed to be useful as buffering, agglomerating or visualization agents. In some cases, it may be advantageous to include sodium chloride, mannitol, polyvinylpyrrolidone or other ingredients in the formulation.

The preferred (ie acid or CD based) formulation method may depend on the physicochemical properties (e.g. aqueous solubility, pKa etc.) of a particular salt. Alternatively, the salt may be presented as a lyophilized solid for reconstitution with water (for injection) or as a dextrose or saline solution. Such formulations are usually presented in unit dosage forms such as ampoules or disposable injection devices. They may also be presented in multidose forms such as a vial from which an appropriate dose may be withdrawn. All such formulations must be sterile.

According to the invention there is provided a process for producing sedation or hypnosis in a subject comprising administering an effective sedative or hypnotic amount of a salt of the invention to the subject.

Also provided in accordance with the invention is a method for inducing an anxiolytic effect in a subject comprising administering an effective anxiolytic amount of a salt of the invention to the subject.

Also provided according to the invention is a process

to induce muscle relaxation in a subject comprising administering an effective anxiolytic amount of muscle relaxant of a salt of the invention to the subject.

Also provided in accordance with the invention is a method for treating seizures in a subject comprising administering an effective anticonvulsant amount of a salt of the invention to the subject. According to the invention there is also provided use of a sedative or hypnotic amount of salt of the invention in the manufacture of a medicament for producing sedation or hypnosis in a subject.

According to the invention there is also provided a salt of the invention for producing sedation or hypnosis in a subject.

Also provided according to the invention is the use of an anxiolytic amount of a salt of the invention in the manufacture of a medicament for producing anxiolytic effect in a subject.

Also provided according to the invention is an inventive salt for producing anxiolytic effect in a subject.

Also provided according to the invention is the use of a muscle relaxant amount of salt of the invention in the manufacture of a medicament for producing muscle relaxation in a subject.

Also provided according to the invention is a salt of the invention for producing muscle relaxation in a subject.

Also provided according to the invention is the use of an anticonvulsant amount of a salt of the invention in the manufacture of a medicament for treating seizures in a subject.

Also provided according to the invention is an invention salt for treating seizures in a subject.

The subject is suitably a mammal, preferably a human being.

human.

A parenteral pharmaceutical preparation suitable for administration to humans preferably will contain from 0.1 to 20 mg / ml of a salt of the invention in solution or multiples thereof for small multidose vials.

Intravenous administration may take the form of bolus injection or, more appropriately, continuous infusion. Dosage for each subject may vary, however, or dosage of a salt of the invention to achieve sedation or hypnosis in a mammal would be 0.01 to 5.0 mg / kg body weight and more particularly 0.02 up to 0.5 mg / kg body weight, the above being based on the weight of salt which is the active ingredient. A suitable intravenous amount or dosage of salt of the invention to obtain anxiolytic effect in a mammal would be 0.01 to 5.0 mg / kg body weight, and more particularly 0.02 to 0.5 mg / kg body weight. , the weight quoted above being based on the weight of salt which is the active ingredient. A suitable intravenous amount or dosage of salt of the invention for muscle relaxation in a mammal would be from 0.01 to 5.0 mg / kg body weight and more particularly from 0.02 to 0.5 mg / kg body weight. body weight above being based on the weight of salt which is the active ingredient. A suitable intravenous amount or dosage of salt of the invention for treating convulsions in a mammal would be 0.01 to 5.0 mg / kg body weight and more particularly 0.02 to 0.5 mg / kg body weight. body, the above weight being based on the weight of salt which is the active ingredient.

Salts of the invention are fast acting CNS sedatives which are useful for intravenous administration in the following clinical situations: preoperative sedation, anxiolytic and anesthetic use for perioperative events; conscious sedation during brief diagnostic procedures, surgery or endoscopy; as a component for inducing maintenance of general anesthesia prior to and / or concomitantly with administration of other anesthetic or analgesic agents; sedation I- CU.

Preferred embodiments of the invention are described in the following Examples with reference to the accompanying illustrations in which: Figure 1 shows a graph of compound content of formula (I) (% relative to initial) vs. storage temperature;

Figure 2 shows Differential Scanning Calorimetry (DSC) of LJC-039-081-1;

Figure 3 shows DSC of LJC-039-081-1 (solid) overlaid with LJC-039-081-2 (dotted); Figure 4 shows DSC of besylate forms (Solid Form,

Dashed form 2);

Figure 5 shows DSC of besylate forms (Solid Form, dotted and dashed Form 3);

Figure 6 shows chromatographs of LJC-039-037-1 at T0 and T4 (and refer to the results in Table 10);

Figure 7 shows XRPD comparing LJC-039-037-1 (salt silicate) before and after stability study for 4 weeks;

Figure 8A shows an XRPD comparison of besylate A Form 1 and 2;

Figure 8B shows Differential Scanning Calorimetry (DSC) overlays of Form 1 and 2; Figure 9A shows an XRPD comparison of Besylate Forma

1 and 3 and

Figure 9B shows overlays of Form 1 and 3; Figure 10 shows DSC of LJC-039-086-1 (Form 4 besylate); Figure 11 shows results for besylate Form 1: A) XRPD for 100 mg batch of LJC-039-037-1;

B) DSC for 100 mg batch of LJC-039-037-1;

C) 100 mg batch TGA of LJC-039-037-1;

D) 1H NMR for 100 mg batch of LJC-039-037-1;

E) GVS for 100 mg batch of LJC-039-037-1;

F) XRPD post GVS for 100mg batch LJC-039-037-1; G)

Post stability XRPD at 40 ° C / 75% RH for 100 mg batch of LJC-039-037-1;

H) VT XRPD for 100 mg batch of LJC-039-037-1;

I) 100 mg batch polarized light microscopy of LJC-039-037-1;

Figure 12 shows results for besylate Form 2:

A) XRPD for 100 mg batch of LJC-039-067-8;

B) DSC for 100 mg batch of LJC-039-067-8;

C) DSC with temperature rise rate of 2 ° C / min; D) 1H NMR for LJC-039-067-8;

Figure 13 shows results for besylate Form 3: A) XRPD for LJC-039-081-2 (2nd crop of LJC-039-081-1 solutions);

Β) DSC for LJC-039-081-2;

C) DSC for LJC-039-081-2 (temperature rise rate of 2 ° C / minute);

D) TGA for LJC-039-081 -2;

E) 1H NMR for LJC-039-081-2;

F) GVS for LJC-039-081-2;

G) XRPD post GVS for LJC-039-081-2;

Figure 14 shows results for besylate Form 4: A) XRPD for LJC-039-086-1;

B) DSC for LJC-039-086-1;

C) 1H NMR for LJC-039-086-1;

Figure 15 shows HPLC chromatography for besylate salt release followed by Agilent ChemStation reports detailing the results;

Figure 16 shows chiral chromatography for LJC-039-081-1 and LJC-039-083-1;

Figure 17 shows examples of images (about 4-8 mm in field of view diameter) of solid forms observed in crystallizations of the compound of formula (I) besylate;

Figure 18 shows the asymmetric unit content in Form 1;

Figure 19 shows molecular structure as determined by single crystal X-ray diffraction of a crystal of the compound of formula (I) besylate, Form 1, formed in a solution of 2-methoxyethanol: pentyl acetate with atoms represented by thermal ellipsoids. . Only hydrogens specifically located in the crystal structure are represented;

Figure 20 shows the conformation adopted by the two independent molecules in Form 1; Figure 21 presents the comparison of the conformation adopted

by an independent molecule in Form 1 (top) and the conformation in Form 2 (bottom); Figure 22 shows the comparison of the conformation adopted by the two independent besylates in Form 1, observed along two different directions;

Figure 23 shows the comparison of the conformation adopted by an independent besylate in Form 1 (top) and the conformation in Form 2 (bottom);

Figure 24 shows the crystal structure, determined by single crystal X-ray diffraction of a crystal of the compound of formula (I) besylate grown from a solution of 2-methoxyethanol: pentyl acetate observed along the crystallographic axis a (a ), axis b (b) and axis c (c);

Figure 25 shows a brief contact C-O 0.6 Ai C-C <3.6 A and N-O <3.5 A for Form 1;

Figure 26 shows calculated powder pattern diffraction from crystal X-ray diffraction data for Form 1; Figure 27 shows applying the shape crystals observed

for the compound of formula (I) besylate Form 2;

Figure 28 shows the asymmetric unit content in Form 2; Figure 29 shows the molecular structure as determined by the single crystal X-ray diffraction of a crystal of Formula (I) besylate compound 2 with atoms represented by thermal ellipsoids. Only hydrogens specifically located in the crystal structure are represented;

Figure 30 shows the conformation adopted by the independent molecule in Form 2; Figure 31 shows the conformation adopted by the independent besylate.

pendant in Form 2, observed along different hard directions;

Figure 32 shows the crystal structure, determined single crystal X-ray diffraction of a crystal of the compound of formula (I) besylated Form 2, observed along crystallographic axis a (a), axis b (b) and axis c (c);

Figure 33 shows a brief contact C-O <3.6 A, C-C <3.6 A and N-O <3.5 A for Form 2; Figure 34 shows calculated powder pattern diffraction from crystal X-ray diffraction data for Form 2;

Figure 35 shows the marking of atomic centers for the compound of formula (I) besylate Form 1 and

Figure 36 shows the marking of atomic centers for the compound of formula (I) besylate Form 2. Example 1

Solid State Stability of the Compound of Formula (I)

Method / Technique. Precision weighed 2 mg samples of compound of formula (I) were placed in small clear glass vials with a 4 mL screw cap. Samples were tested at baseline and after 34 days stored at 5 ° C / Relative Ambient Humidity (AMRH) Closed, 30 ° C / 60% RH Closed, 40 ° C / 75% Open RH and 60 ° C / AMRH Closed

The samples were visually inspected for appearance. The content values of the compound of formula (I) were determined by HPLC method in Table 1. The values of% weight / weight (% weight / weight) were measured relative to standardized samples of compound of formula (I) batch. U12438 / 79/1. The% area values were obtained by dividing the peak area of the compound of formula (I) by the total peak area.

Table 1. HPLC Method Condition

Column: Phase = Length χ i.d. = Particle Size = Phenomenex Luna C18 (2) 100x4.6mm 3 Mm Mobile Phase: A = 10OO: 1 Water / Trifluoroacetic Acid B = 1000: 0.5 Acetonitrile / Trifluoroacetic Acid Flow Rate: 1.0 ml / min Column Temperature : 40 ° C Gradient Time (minutes)% A% B 0.0 80 20 20.0 20 60 25.0 20 60 25.1 80 20 30.0 80 20 Detection Wavelength: 230 mm Injected Sample Mass 1.0 pg, typically 1 μΙ_ injection of 1.0 mg of compound of formula (l) / mL in 60:40 Water / Acetonitrile Retention Times The compound of formula (I) elutes around 7.64 minutes RESULTS Appearance. Table 2 relates Table 2. Summary of Dads: ion appearance results. Compound Appearance Formulas (I) Storage Condition Time Point Appearance (days) Ambient Temperature Initial Light Cream Powder 5C / AMRH Closed 34 Light Cream Powder 30C / 60% RH Closed 34 Powder Cream light yellow 40C / 75% RH Open 34 Yellow liquefied pasta at the bottom of the small jar 60C / AMRH Closed 34 Dark yellow to orange liquefied pasta at the bottom of the small jar

Compound content of formula (I) (wt% / wt). The% weight / weight content values (see Table 3) demonstrate too much variability to detect differences between baseline and those measured after 34 days at 5 ° C / AMRH Closed, 30 ° C / 60% RH Closed or 40 ° C / 75% RH Open. The average weight / weight measured for samples stored 34 days at 60 ° C / AMRH Closed show a 10% decrease in weight / weight from baseline.

Compound content of formula (I) (% area). The% area content of the compound of formula (I) (see Table 3 and Figure 1) shows no significant variation after 34 days stored at 5 ° C / Closed AMRH, but decreases steadily with increasing temperature. Sample storage at 30 ° C / 60% RH Closed, 40 ° C / 75% RH Open or 60 ° C / AMRH Closed. The main degradation peaks are observed at picoRRT 0.68, 0.87 and RRT 0.90, but chromatograms, which are relatively complex even at the beginning (23 peaks), also show many new small peaks of peak degradation ( 7 peaks at 30 ° C / 60% RH Closed; 13-20 peaks at 60 ° C / Closed AMRH). These observations suggest multiple degradation pathways. The RRT degrading agent 0.68 is temporarily identified as the product of ester hydrolysis (the free acid of the compound of formula (I)). This is more prevalent in open samples at 40 ° C / 75% RH, as would be expected for a hydrolysis product.

Table 3. Summary of HPLC Data for Compound of Formula (!)

Storage Condition Time point Compound Content of Formula (I)% Relative to% of Area Initial Average Days% in weight / weight% of Area Initial Average 100.5 95.14 Avg = 94.81 Average Starts ! 104.1 94.47 5C / AMRH Closed # 11 34 102.6 95.30 100.52 30C / 60% RH Closed # 11 34 94.7 94.20 99.36 40C / 75% RH Open # 1 34 105 , 93.45 98.57 40C / 75% RH Open # 2 34 100.3 93.39 98.59 60C / AMRH Closed # 1 34 93.4 87.77 92.57 60C / AMRH Closed # 2 34 91 , 87.77 92.57

Grades

1. Only one sample was tested due to autosampler error following

quentador.

CONCLUSIONS

The compound of formula (I) is stable in appearance and

content for at least 34 days storing at 5 ° C / AMRH Closed. No change in appearance was observed at 30 ° C / 60% RH Closed, but a decrease of approximately 0.6% in the compound content of formula (I) relative to the initial area% was observed. Samples stored at 40 ° C / 75% RH open or 60 ° C / AMRH Closed melted to yellow to orange and showed remarkable decreases (1.5 to 8%) in the compound content of formula ( I) concerning the initial. The main degradation peaks at RRT 0.68, 0.87 and RRT 0.90 are observed along with smaller peak numbers, suggesting multiple degradation pathways. The degradant RRT 0.68 is tentatively identified as the ester hydrolysis product. These results indicate that the compound of formula (I) should be stored refrigerated for long term storage. Example 2

The solubility of the compound of formula (I) was determined over a wide range of organic solvents. Solubility data are presented in Table 4 below.

Table 4

Solvent Min of solvent needed / mg / ml Methanol 446 Ethanol 324 Propan-2-ol 454 Acetone 214 Toluene 460 Ethyl acetate 218 Tetrahydrofuran 311 Acetonitrile 362

The data clearly demonstrate that the compound of formula (I) has high solubility in common organic solvents. Preferred solvents are ethanol and toluene.

Two basic centers of a free base of the compound were measured for pKa. However, the basic center of the pyridine ring had a pKa of 1.99. The pKa of the basic center of the imidazole ring was measured and is 4.53.

Benzenesulfonic acid was used to produce the besylate salt of the compound of formula (I). Experiments were conducted on a 20 mg scale using 6 volumes of solvent. All reactions were performed at temperature with charged acids as stock solutions in ethanol (1M) or as solids depending on solubility.

Isolated solids showed significant peak shifts in 1H NMR to confirm salt formation. An X-ray diffraction pattern (XRPD) showed that the salt had a crystalline indication. Table 5 summarizes the isolated salt form. Table 5

Input Salt Solvent ID 1 besylate toluene LJC-039-009-7

The salt was subsequently stored at 40 ° C / 75% RH for

for two weeks then reanalyzed by XRPD and HPLC for chemical purity to assess material stability. Salt retained the same dust pattern after exposure to wet conditions and also maintained the same high chemical purity ensuring improved stability.

It can be seen from the T1 purity results of the salt alone (Table 6 below) that the besuylate salt from toluene had high purity values before and after the stability study. Table 6 Purity summary before and after 40 ° C / 75% RH for 1 week

Home Salt Salt Purity T °% Purity T 1% 1 besylate LJC-039-009-7 95.9 95.9

The above results demonstrate that the besylate salt form showed great purity and favorable stability results. Example 3

Increasing the amount of besylate salt to 100 mg was performed based on the data in Example 2. It has been found that toluene is the preferred solvent for isolating besylate salts. Besylate salt of compound of formula (!)

An increase in the amount to 50 mg of input material was performed to confirm whether or not the process could be expanded and to confirm that the isolated material was the same crystalline Form (Form 1) observed by the previous experiment on a smaller scale. Once the analysis confirmed the salt as Form 1 and the properties were maintaining what was expected, another 100 mg amount of input material was amplified to complete and complete characterization. subject the sample during a 4-week stability study at 40 ° C / 75% RH. The reaction quantity was increased as a solution in toluene with added benzene sulfonic acid and in a solution in ethanol (1 M). Besylate Experimental Procedure

The compound of formula (I) free base (100 mg, batch 704-17) was charged to a small vial and toluene (600 μΙ) was added at room temperature. Benzenesulfonic acid solution (250 μΙ, 1 M in ethanol) was added and the reaction mixture stirred for fifteen minutes, after which time a solid had precipitated from the solution which was filtered, washed with toluene and oven dried at 40 °. C under vacuum. XRPD analysis showed that the solid is of the same powder standard as the other besylates generated and 1H NMR confirmed salt formation due to significant peak deviations.

Table 7

Entry GVS uptake salt ID /% Melting onset / ° C TGA weight loss /% Solubility mg / ml Chemical purity /% Chiral purity /% e.e. 1 LJC-039-037-1 Besylate 2.0 201.3 4.9 8.3 97.1 94.4

The enantiomeric excess for LJC-039-037-1 was only 94.4 so the result was compared to another besylate batch (LJC-039-081-1) which was isolated under identical conditions. The enantiomeric excess of this batch was 99.1%. Process Optimization

To further improve the yields of besylate salt (Form 1) four solvents (isopropyl acetate, ethyl formate, methanol and acetone) were selected. Eight reactions on the 100 mg scale were conducted in these solvents with the relevant acid and added as stock solution in ethanol for comparison with previous experiments.

The compound of formula (I) (batch 704-38, 100 mg) dissolved in solvent (600 μΙ) at room temperature. Acid (250 μΙ, 1 Μ, ethanol stock solution) added and all reaction mixtures remained 48 hours in the environment. The results are summarized in Table 8.

Table 3 Results of Process Optimization Experiments Table Entry Reference in Lab Book Salt Solvent XRPD Yield /% Purity /% Post Purity 40 ° C / 75% RH for 4 weeks 1 LJC-039-067-2 Besylate Acetone Forma 1 38 98.4 98.1 2 LJC-039-067-4 Besylate i PrOAc Form 1 79 97.7 95.9 3 LJC-039-067-6 Besylate Ethyl formate Form 1 40 98.6 98.3 4 LJC-039-067-8 Besilate MeOH Isolated Crystals, Form 2 Not Registered 98.1 Not Registered

All reactions except that of besylate formation in

methanol were Form 1. The reaction with methanol was stored at 4 ° C. The data obtained confirmed anhydrous besylate 1: 1 and a dust pattern of the material confirmed the existence of a new Form (Form 2).

It was concluded from the study that solvents such as isopropyl acetate increased the purity of salts, but reduced recovery. Since the previous choice of solvent (ethyl acetate) provided high yields of salts with high purity values, it was decided to use ethyl acetate for the final amount increase experiments. Besylate (Form 1) Increase the amount to 1 g

A formation of 1 g of the besylate salt was performed. This successfully yielded 950 mg (70% yield) of Form 1. The solutions were quite colored (yellow) and therefore seeded with a small amount of Form 1 to aid recovery. The solutions were stored at 4 ° C for 16 hours. The solid obtained showed a new powder pattern (Form 3). The solid was analyzed by thermal analysis and variable temperature XRPD to confirm whether it was a true polymorph or a solvate. Interpretation of the analysis concluded that it was not a solvate by 1 H NMR evidence and DSC showed two endothermic events. confirmed by hot stage microscopy (Figure 3). Form 1 seeds were interpreted to melt at 187 ° C, with Form 3 to melt at 200 ° C. The reason Form 1 has not been identified by XRPD is that this is a less sensitive technique than microscopy.

Form 3 precipitates at a lower temperature than

Form 1

The characterization was performed in the polymorphs to propose the relationship between them. Table 9 Besylate Form Thermal Data _

Entry ID Shape Beginning of the Formation / X ΔΗ / Jg "1 1 LJC-039-081 -1 1 201 56 2 LJC-039-067-8 2 180 73 3 LJC-039-081-2 1,3 187, 200 7.6, 37

The lowest melting point of the small amount of Form 1

present in LJC-039-081-2 can potentially be attributed to lower purity (97.2% compared to 97.9% in LJC-039-081-1).

Figure 4 shows the DSC of forms 1 (solid) and 2 (dashed)

of besylate.

Figure 5 shows the DSC of forms 1 (solid) and 3 (dotted and dashed). Example 4

Salt Stability Studies

Table 10 Summary of salt purity after 4-week stability study

Sample ID Salt T0 T1 T2 T3 T4 LJC-039-037-1 Besylate 97.1 97.3 97.4 96.7 96.7

Crystalline besylate samples were stored at 40 ° C / 75 ° C.

% RH for a total of four weeks and HPLC samples were taken every seven days. The purity of besylate HPLC remained consistent until T3 when it reached 96.7%.

This value however remained consistent until T4. HPLC chromatographs for the besylate salt form are

shown in figure 6 for week zero and week four time points.

It is suspected that the dominant peak before the original peak is due to contamination when Amax does not match the Amax of the original peak. It is also missing from the T11 T21 T3 and T4 impurity profile.

It can be observed by the standards of pre and post moisture salt powder studies that there are no changes in shape.

Figure 7 shows XRPD comparing LJC-039-037-1 (besylate salt) pre and post stability study for 4 weeks. Example 5

Polymorphism Investigation

To determine the propensity of besylate salts to exhibit polymorphism, a maturation experiment using thirty solvents (fifteen pure plus their 2.5% aqueous counterpart) was installed. The solid was suspended in various solvents (see Table 11) for one week over a heat / cold cycle from room temperature to 60 ° C. After one week the suspensions were evaporated and the solids analyzed by XRPD and HPLC.

Table 11 Investigation results of besylate polymorphism (LJC-039-058-2)

Solvent entry XRPD after 1 week HPLC purity / area% 1 Acetone Form 1 97.5 2 THF Form 1 97.6 3 IPA Amorphous 97.1 4 MtBE Form 1 97.7 DCM Amorphous 97.4 6 EtOH Oil Not analyzed 7 MEK Form 1 97.2 8 1,4-dioxane Form 1 97.2 9 iPrOAc Form 1 97.5 DMF Oil Not analyzed 11 MeCN Form 1 94.3 12 NbuOH Oil Not analyzed 13 nPrOH Oil Not analyzed 14 MIBK Form 1 97.7 MeOH Oil Not analyzed 16 2.5% acetone aq. Form 1 96.8 17 2.5% THF aq. Amorphous 93.3 18 2.5% IPA aq. Form 1 76.1 19 2.5% MBE aq. Oil Not analyzed 2.5% DCM aq. Form 1 97.4 21 2.5% EtOH aq. Oil Not analyzed 22 2.5% MEK aq. Form 1 93.9 23 2.5% 1,4-dioxane aq. Form 1 86 24 2.5% iPrOAc aq. Oil Not analyzed 2.5% DMF aq. Oil Not Analyzed 26 2.5% MeCN aq. Form 1 93.3 27 2.5% nBuOH aq. Oil Not Analyzed 28 2.5% ηPrOH aq. Oil Not Analyzed 29 2.5% MBK aq. Form 1 97.3 2.5% MeOH aq. Oil not analyzed

The maturation study using besylate salt has not revealed new forms. Post-maturity purity results show that those suspended in acetonitrile, aqueous THF, aqueous IPA, aqueous MEK, aqueous dioxan and aqueous acetonitrile degraded. This suggests that the besylated salt (Form 1) has good solution stability in pure high temperature organic solvents.

Investigating new forms of besylate

Although no new forms of the besylate salt were observed by the maturation study, a new form was observed when crystals grow in methanol. The simple crystals obtained with methanol were milled to obtain a powder pattern. This pattern became different from Form 1. A repeated experiment was performed to obtain another supply of Form 2. It was only possible to isolate Form 2 from precipitation for 16 hours from the solutions, as opposed to allowing the solvent to evaporate, i.e. - says Form 1. Interestingly, two presentations were present: needles and blocks. Both showed the same powder pattern as the needle presentation that was used to determine the single crystal structure.

The complete analysis was performed on Form 2. This was found to be a true polymorph as confirmed by the simple anhydrous besylate crystal data 1: 1.

Figure 8A shows an XRPD comparison of besylate Forms 1 and 2. There is no obvious difference between Form 1 (feature 1) and Form 2 (feature 2). As can be seen from the two dust patterns, both shapes are very different. Thermal analysis was performed to compare the melting points of the two forms and thermodynamic solubility measurements were also recorded.

Figure 8B shows overlaps of Forms 1 and 2. Forms 1 and 2 show an endothermic event (fusion).

Form 3 was identified when a second crop was isolated from LJC-039-081-1 solutions (reaction extended to 1 g). Analysis was performed to determine whether or not it was a solvate and how the forms are converted to each other.

Figure 9A shows an XRPD comparison of Formal and Besylate 3. Figure 9B shows overlaps of Forms 1 and 3.

Form 1 has one endothermic event (fusion), while Form 3 has two events. Hot stage microscopy on Form 3 clearly shows two fusions within 20 ° C of each other. It is postulated that the small amount of the lower melting polymorph is present as if it were not captured in XRPD at a variable temperature, which is a less sensitive technique. It is entirely possible that the first endothermic event represents Form 1 because it was used to sow the solutions from which Form 3 was isolated.

Solubility data demonstrate that all three forms have very similar aqueous solubilities of from 7.8 to 8.3 mg / ml at pH 3.

Besylate salt Form 4

The besylate salt release batch Form 1 (LJC-039-083-1) was of high purity (97.6%) but contained a small amount of impurity entrained through a free base (0.78%, 11%). 9 minutes at room temperature). This impurity was observed in the DSC experiment presenting an endothermic transition (beginning at 130 ° C). The peak was confirmed to have an Amax unrelated to the original peak.

A 100 mg sample was taken for a recrystallization attempt of 40% isopropyl acetate / ethanol. Recrystallization was traditionally performed by dissolving the salt in the minimum amount of hot solvent, then slowly cooling to room temperature to provide a precipitate. The dried solid was analyzed by XRPD which indicated a new form and with thermal analysis and 1H NMR was confirmed to be a polymorph and not a solvate. Figure 10 shows DSC of LJC-039-086-1.

Salt selection investigations have shown that the compound of formula (I) forms many salts within the appropriate pKa range and that these are easily isolated with a range of solvents. Due to the total characterization of the salts, it was determined that the besylate salts had good stability in relation to humidity. It was then concluded that there are two polymorphic forms of besylate. Form 3 came from the second crop of LJC-039-081-1 solutions after sowing with Form 1. Form 4 was observed after a recrystallization of Form 1 was made from 40% acetate. isopropyl / ethanol. The complete analytical data are presented in figures 11 -

14 below.

Experimental Methods for Examples 2-5 Example 2

The compound of formula (I) (5 mg / well) was dissolved in solvent 1 (30 μΙ) in small HPLC flasks. To the solutions, benzenesulfonic acid (11.4 μΙ, 1 M methanol) was added and the reaction mixtures were left overnight at room temperature. Those small flasks containing solid were dried at 40 ° C under vacuum and the solutions of those that remained were concentrated by evaporation and then treated with heptane. Those that precipitated were dried as mentioned and those that remained as oil were stored at 4 ° C. Increased amount of besylate Form 1

The compound of formula (I) (100 mg) dissolved in ethyl acetate (600 μΙ) and benzenesulfonic acid (250 μΙ, 1 M in ethanol) added. Precipitation occurred instantaneously and the reaction mixture was stirred.

1 Ethanol, toluene and acetonitrile for 24 hours at room temperature. The solid was filtered, washed with ethyl acetate and oven dried at 40 ° C under vacuum for 16 hours. Analysis Methods

Differential Scanning Calorimetry (DSC) DSC data were collected under a TA instrument.

Q1000 equipped with a 50 position autosampler. The energy and temperature calibration standard was Indian.

The samples were heated at a rate of 10 ° C / min between 25 and 350 ° C. A 30 ml / minute nitrogen purge was maintained over the sample.

Between 0.5 and 3 mg of sample were used, unless otherwise stated and all samples were treated in an aluminum vat with small holes. Thermogravimetric Analysis (TGA) TGA data were collected on a TA Q500 Instrument

TGA, calibrated with Alumel and operating at investigation rates of 10 ° C / min. A 60 ml / min nitrogen purge was maintained over the sample.

Typically 5-10 mg of sample was loaded onto a pre-tared platinum crucible unless otherwise determined. NMR

All spectra were collected on a Bruker 400 MHz equipped with autosampler. Samples were prepared in CZ6-DMSO unless otherwise indicated.

stated otherwise. XRPD (Powder X-ray Diffraction) Bruker AXS C2 GADDS Diffractometer

X-ray diffraction patterns for the samples were obtained on a Bruker AXS C2 GADDS diffractometer using Cu Ka radiation (40 kV, 40 mA), automated XYZ stage, laser video microscope for sample self-positioning and a HiStar 2 dimensional area detector. X-ray Optics consists of a simple multi-layer Göbel mirror coupled with a 0.3mm pinhole collimator.

Beam divergence, that is, the effective size of the x-ray beam on the sample was approximately 4 mm. A continuous Θ-Θ scan mode with a 20 cm sample to detector distance providing an effective 2 que range of 3.2 - 29.8 ° was employed. A typical exposure time of a sample would be 120 seconds.

Samples operating under ambient conditions were prepared as flat specimens using the powder as received without grinding. Approximately 1-2 mg of the sample was pressed onto a glass slide to obtain a flat surface. Samples operating under non-ambient conditions were mounted on a thin plate of silicon with heat conductive compound. The sample was then heated to the appropriate temperature around 20 ° C / minute and subsequently isothermally maintained for about 1 minute before data collection was started. Purity Analysis: Chemical Method

Purity analysis was performed on an Agilent HP1100: Method: Gradient, Reverse Phase Method Method Duration / min: 34

Column. Phenomenex Gemini C18 5 μιτι (2.0 χ 50 mm) (Guard cartridge Phenomenex Gemini C18 2 χ 4 mm cartridge guard) Column Temperature / ° C: 40 lnjection / μΙ: 5

Flow ml / min: 0.8 Detection: UV

Wavelength / nm: 255 (90 nm bandwidth), 240 (80 nm bandwidth), 254 (8 nm bandwidth)

Phase A: 2 mmoles NH4HCO3 (adjusted to pH 10 with NH3 solution) Phase B: Acetonitrile Timesheet:

Time / Minutes% of A% of B 0 90 10 10 90 28.8 10 90 29 90 10 34 90 10

Chiral Method

Purity analysis was performed on a Gilson HPLC system: Method: Isocratic, Normal Phase

Method Duration / min: 50

Column: Diacel Chrialcel OJ-H (5 μηι) 4.6 χ 250 mm (Guard cartridge Diacel Chrialcel OJ-H Analytical guard cartridge 5 Mm 4.0 χ 10 mm) Column Temperature / ° C: 40 lnjection / μΙ: 10 Flow ml / min: 1.0 Detection: UV

Wavelength / nm: 225 (single wavelength detector) Phase A: Hexane Phase B: Ethanol Time Table:

Time / Minutes% of A% of B 0 93 7

Gravimetric Studies of Steam Sorption (GVS)

All samples were used on a Hiden IGASorp moisture sorption analyzer that works with the CFRSorp computer program. Sample sizes were typically 10 mg. A moisture desorption adsorption isotherm was performed as outlined below (2 tests providing 1 complete cycle). All samples were loaded / discharged at typical ambient humidity and temperature (40% RH, 25 ° C). All samples were analyzed by XRPD after GVS analysis. The standard isotherm was performed at 25 ° C at 10% RH intervals in a range of 0 - 90% RH unless otherwise stated.

Exam 1 Exam 2 Adsorption Desorption Adsorption 40 85 10 50 75 20 60 65 30 70 45 40 80 35 90 25 15 5 0

Solubility

This was measured by suspending sufficient compound in 0.25 ml solvent (water) to provide a maximum final concentration of 10 mg / ml of an original free formed compound. The suspension was equilibrated at 25 ° C for 24 hours followed by a pH control and filtration through a 96-well fiberglass C plate. The filtrate is then diluted to 101 χ. Quantitative assessment was done by HPLC with reference to a standard dissolved in DMSO around 0.1 mg / ml. Different volumes of standard diluted and undiluted tests were injected. Solubility was calculated by integrating the peak area found at the same retention time as the maximum peak in the standardized injection. If there is sufficient solids in the filter plate, XRPD is normally controlled for phase variations, hydrate formation, amortization, crystallization, etc.

Table:

Time / Minutes% A% B 0.0 95 5 1.0 80 20 2.3 5 95 3.3 5 95 3.5 95 5 4.4 95 5

PKa determination

The determination of pKa was performed on a D-PAS-linked Sirius GIpKa instrument. They were measured by potentiometric titration in mixtures of MeOH / H2O at 25 ° C. The ionic concentration of the titration medium was adjusted with 0.15 M KCI. The values found in the MeOHiH2O mixtures were extrapolated to 0% cosolvent by a Yasuda-Shedlovsky extrapolation. Hot Stage Microscopy

Hot stage microscopy was studied using a Leica LM / DM polarized microscope combined with a Mettler-Toledo MTFP82HT hot stage in the temperature range 25-50 ° C with typical heating rates in the range 10 - 20 ° C. C / min. A small amount of sample was dispersed on a glass slide with separate individual particles as much as possible. Samples were observed under normal or cross-polarized light (coupled to a false color filter λ) with a χ 20 objective lens. Chiral Purity Method System Installation Pump: Gilson Binary Pump 322 Detector: Gilson 152 UV / Vis

Autosampler: Gilson 233XL Stand + Gilson Double Syringe Pump 402 Greenhouse Speaker: Phenomenex Thermasphere TS-130 Computer Program: Gilson Unipoint LC Speaker: Daicel Chiralcel OJ-H, 5 Mm, 4.6 χ 250 mm Guard Speaker: Daicel Chiralcel OJ-H analytical cartridge guard, 5 μπι, 4.6 χ 10 mm HPLC Conditions Channel A: Hexane (93%) Channel B: Ethanol (7%) Flow Rate: 1.0 ml / min Detector Wavelength 225 nm Column Temperature: 40 ° C Run Time: 50.0 minutes Sample Conditions

Approximately 0.2 mg of sample was dissolved in the appropriate 1: 1 v / v hexane: ethanol volume to provide a 0.2 mg / ml solution. It was capped and placed in a high speed vortex mixer for a period of approximately 15 seconds. If the solid remained at this point, then the small sample vial was sonicated for approximately 10 seconds followed by an additional 10 to 15 seconds in the vortex mixer. 10 μΙ were injected into the HPLC system. Samples were injected in duplicate after an initial duplicate injection of 1: 1 v / v Hexane: ethanol as a blank assay. Example 5

Pharmacological Test Example The anesthetic and sedative effects of the salt

Iato Form 1 of the present invention. The besylate salt (from benzenesulfonic acid) was dissolved in saline for administration of the test composition to the animal. The test composition was administered to mice placed in individual Plexiglas cages (20 χ 10 χ 10 cm). The mice were injected with vehicle or test substance intravenously. Latency to sleep and duration of anesthesia (maximum: 90 minutes after test substance administration) were recorded. Anesthesia is indicated by the loss of righting reflex (LRR). The righting reflex test was performed long and the animals appear silky, approximately every 20 - 30 seconds. Once the righting reflex was absent, the duration of the righting reflex loss was measured by testing for the return of the righting reflex approximately every 20 - 30 seconds thereafter. Eight mice per group were studied and the test was performed blindly. Study results are provided in the following table. TREATMENT (mg / kg) i.v. NUMBER OF Mice WITH LRR LATENCE TO LRR (min) LRR DURATION (##) average + s.e.m. (#) average + s.e.m. (#) value of ρ Vehicle 0.0 + 0.0 CNS 7056X besylate (20.4) 2 - 1.7 + 1.3 NS 0.141 CNS 7056Χ besylate (27.2) 5 + 3 .0 + 0.2 4.9 + 1.6 * 0.0106 CNS 7056X besylate (34) 6 ++ 1.8 + 0.2 6.0 + 1.9 "0.0038 CNS 7056X besylate broad (40.8) 6 ++ 1.6 + 0.5 7.3 + 2.5 ** 0.0038

Mann-Whitnev U Test: NS = Not Significant; * = ρ <0.05; ** = ρ <0.01 Fisher's exact test (number of mice with LRR): no indication = not significant; + = ρ <0.05; ++ = ρ <0.01

(#): not calculated if η <3

(##): maximum = 90 minutes after injection

The results in the table above demonstrate that Form 1 besylate salt has a rapid latency until the loss of righting reflex and therefore a short induction time until anesthesia in animals. In addition mice recover rapidly from anesthesia as indicated by the rapid duration of loss of righting reflex. Thus, this compound can provide rapid induction and recovery of anesthesia. Example 6

Additional Conditions for Crystallization of Forms 2, 3, and 4

Additional conditions were tested in an attempt to reproduce the previously reported crystallizations of Forms 2, 3 and 4. However, the reported scales were substantially reduced and the Methodology modified accordingly, as described below. Form 2

mg of solid was dissolved in 25 µl methanol and 10 µl ethanol added; The solution was then cooled to 4 ° C for 3 days.

Form 3

Three variants were tried:

1.5 mg of solid was dissolved in 50 µl ethanol and 120 µl ethyl acetate added; The solution was then cooled to 4 ° C for 3 days.

2. 10.1 mg of solid was dissolved in 300 µl ethanol and 120 µl

ul of ethyl acetate added; The solution was then cooled to 4 ° C for 3 days.

3. 2.5 mg of solid was dissolved in 50 µl ethanol in a small silanized flask and 100 µl ethyl acetate added; the solution

The reaction was then cooled to 4 ° C for 3 days. Form 4

Three variants were tried:

1. A heated (70 ° C) mixture of isopropyl acetate: ethanol (40%: 60% v / v) was added to 5 mg of heated solid in aliquots of

20 µl until solid dissolved (60 µl total solvent mixture); The solution was then allowed to slowly cool to room temperature in an initially thermostated water bath at 70 ° C over a period of hours.

2.5 mg of solid was dissolved in 180 µl (50 ° C) of

isopropyl: ethanol (40%: 60% v / v) solvent and the solution allowed to cool

slowly to room temperature in a thermostated water bath (initially at 50 ° C) over a period of hours.

3. A 5 mg portion of solid was dissolved in 100 µl of heated solvent (50 ° C) isopropyl acetate: ethanol (40%: 60% v / v) in

a small silanized flask and the solution allowed to slowly cool to room temperature in a thermostated water bath (initially at 50 ° C) over a period of hours. Each of the crystallizations provided solid material with blade and plate appearances, with Form 4 crystallizations providing needle-like material. Example 7

Characterization of compound (!) Besylate

The compound of formula (I) besylate is chiral and is assumed to be of the following simple enantiomeric form, that is, the S enantiomer (consistent with the subsequently determined crystal structures):

The compound of formula (I) besylate is chiral and is supposed to be

of the following simple enantiomeric form, that is, the S enantiomer (consistent with the subsequently determined crystal structures):

The heterocyclic structure contains a basic nitrogen in the imidazole ring (pKa of 5) and a weaker basic nitrogen in the pyridyl ring (pKa around 2). Imidazole nitrogen will typically be protonated in the presence of strongly acidic besylate (pKa around 0.6) in aqueous solution, with pyridyl nitrogen also potentially being protonated under besylate excess conditions.

The neutral free base (i.e. protonated) base form of the compound is expected to be somewhat lipophilic (\ oPPoctanoi / water around 4.0) and thus would prefer some lipophilic environments over aqueous ones. In addition, a degree of lipophilicity is likely to be maintained even when monoprotonated (log D Octanoi / water ca. around 2 to pH 3), although the effect of the besylate indicator ion is likely to improve this trend through its inherent hydrophilicity. The degree of lipophilicity also decreases to the diprotonated form (10% octagonal water / pH about 0.6 at pH 0).

The compound also has an excess of hydrogen bond acceptors and therefore will be suitably shared by hydrogen bond donor solvents. The compound is thus expected to prefer solubilization in a range of polar organic solvents such as alcohols, particularly those which provide a binding donor environment.

of partially Iipophilic hydrogen. This was confirmed by experimental evidence (details of the solvents used are given in Example 8):

Solvent Observed solubility (mg / ml) Formamide 350 Water 2 Dimethyl sulfoxide 500 Dimethylacetamide 200 1,2-ethanediol 60 Dimethylformamide 300 Acetonitrile> 20 Methanol 400 2-ethoxyethanol 20 2, 2,2-trifluoroethanol 1000 Ethanol 100 Acetone 2 Propane-1 -ol 15 Propane-2-ol 4,8 2-methoxyethanol 167 Hexafluoropropane-2-ol> 700 Dichloromethane «0.3 Tetrahydrofuran 2.5 Methylbenzoate 2 Ethyl acetate 0.2 Chloroform« 0.4 1,4-Dioxane 1

Soluble (> 5mg / ml), partially soluble (2.5 - 5 mg / ml), partially insoluble (0.5 - 2.5 mg / ml, insoluble (<0.5 mg / ml)).

The quoted values are approximate but experimentally confirmed.

These results highlight the good solubility of the compound in

a wide variety of polar organic solvents. In particular, 2,2,2-trifluoro ethanol and hexafluoropropan-2-ol are both identified as extremely good solvents for this compound. This is consistent with the considerations discussed above, both solvents being strong hydrogen bond donors. Similarly, the most substantially lipophilic solvents are identified as potential antisolvents for crystallization.

Example 8

Crystallizations of the compound (!) Besylate Several conditions are described which lead to the obtaining of the material.

The crystalline conditions of the compound of formula (1) besylate Forms 1 and 2. Crystallization conditions which include alcohol or acetonitrile solvents as components, with their respective compatible antisolvents or cosolvents, are believed to provide the most promising conditions for providing - cer a crystalline material. Crystallization using binary solvent / antisolvent mixtures was mainly used. Crystallizations were performed by delayed evaporation of the sub-cured solutions of the compound in solvent / antisolvent mixtures at reduced room temperature (4 ° C). Crystallization was typically observed within 3-5 days of preparation.

When the amount of sample allowed, all crystallization conditions were performed in duplicate in a 96-well glass plate format; half of each well plate being used to duplicate conditions on the other half of the well Cross contamination between wells is minimized by the project. All conditions tested reproducibly behaved in at least duplicate, most providing adequate solid material for further analysis.

In all cases, sample contact equipment and crystallization media were scrupulously cleaned with a variety of solvents and reagents before being bathed in ethanol and dried insufflated using evaporated copious nitrogen.

High quality solvents from commercial suppliers were employed as described in Table 12.

Supplier Solvent No. from cat. Grade No. Purity Grade 1,2 dichlorobenzene Romil H177 E558470 SpS> 99.8% 1,4-dimethylbenzene Fluka 95682 429739/1 Puriss ps> 99% 1,4-dioxane Romil H297 H540480 SpS> 99.9 % 2,2,2-2-trifluoroethanol Romil H860 M538412 SpS> 99.9% acetonitrile Romil H049 D531490 SpS> 99.9% dimethylacetamide Romil H249 B540480 SpS> 99.9% dimethyl sulfoxide Romil H280 W530480 SpS> 99.9 % ethanol Romil H314 0533480 SpS> 99.8% ethyl acetate Romil H346 T533480 SpS> 99.9% methyl iso-butyl ketone Romil H446 M539430 SpS> 99.9% n-nonane Romil H568 0558450 SpS> 99.9 Fluka% pentyl acetate 46022 13248/1 Puriss> 98.5% propan-1-ol Romyl H624 G531460 SpS> 99.9% propan-2-ol Romyl H625 0530480 SpS> 99.9% tetrachlorethylene Romil H702 W536450 SpS> 99.9% tetrahydrofuran Romil H718 B532470 SpS> 99.9% acetone Romil H031 E559470 SpS> 99.9% chloroform Romil H135 B554470 SpS> 99.9% dichloromethane Romil H202 0554460 SpS> 99.9% dimethylformamide Romil H25S T546460 99.9% formamide Romil H351 Q5374 80 BioPure> 99.9% hexafluoropropan-2-ol Romyl H359 H559470 SpS> 99.9% Fluka methyl benzoate 12460 417868/1 Purum> 98% Water Romil H950 D537480 SpS> 99.9%

Visual analysis of the resulting crystalline morphologies was con-

followed by using a binocular microscope (magnification around 10 χ - 40 χ) with attached digital camera, which employs both transmitted and reflected light when appropriate.

The visual characterization of solid material is summarized in Table

beautiful 14 below. A predominance of lamina or tabular / plaque morphologies was observed, either as isolated crystals or as spherulites. Above all, there is little morphological difference between the crystallizations performed at room temperatures and those at 4 ° C, except for those with ethanol as solvent where the tendency for spherulite and interface growth decreased with the decrease. of temperature. It is noteworthy that the use of anti-solvent can substantially improve the quality of crystalline material.

Examples of images of crystalline material observed are shown in Figure 17. As illustrated in this figure, acetonitrile has a tendency to produce spherulite growth, typically considered as a consequence of poor nucleation and thus growth of low crystal surfaces. quality. In contrast, 2-methoxyethanol has a tendency to produce isolated blade / needle-like morphology crystals.

It seems to be a general preference for Form 1 to crystallize under many conditions. However, it is noteworthy that Form 2 was also observed from various crystallization conditions, including the smaller scale analogies for obtaining Forms 3 and 4 (described in Example 6). Form 2 is observed under conditions where there are extremes of polarity (acetonitrile: water) or lipophilicity (n-nonane) or both (dimethyl sulfoxide: 1,2-dichlorobenzene). Overall, Form 2 crystals were notable in their superior quality and distinct well-formed plate / tabular presentation.

Isolated Crystal X-Ray Diffraction Cell Determinations To provide corroborative evidence of the crystalline forms generated by

From these, the cell parameters of certain crystals of adequate quality were determined using the χ ray diffraction of the crystal. The crystal unit cell parameters were determined using a Mo-radius Kappa CCD diffractometer, the crystals mounted on an oil-glass fiber and kept at 260 K. The parameters for Form 1 and Form 2 were determined as summarized in Table 13.

Table 13. Cell parameters determined for crystals of the compound of formula (!) Besylate.

Form 1 Form 2 Crystal Status Solvent 2-methoxyethanol ethanol Antisolvent / Cosolvent pentyl acetate ethyl acetate Needle plate morphology Crystal Size (mm) 0.8x0.04x0.02 0.7x0.3x0.25 Color Colorless Colorless Structure do Cristal Orthorhombic monoclinic system Single cell a (Á) 7,6868 (1) 8,92130 (10) b (Â) 29,2607 (5) 11,1536 (2) c ((A) 12,3756 (3) 25.8345 (4) oc (°) 90 90 PH 97.7880 (8) 90 y (°) 90 90 Volume (A3) 2757.89 (9) 2570.65 (7)

The crystallization results with solvent / cosolvent and solvent / antisolvent conditions for the compound of formula (I) be silate with the results of the crystal X-ray diffraction unit cell are tabulated in Table 14.

Table 14. Experimental results of crystallization of solvent / coarse Ivente and solvent / anti-solvent conditions for the compound of formula (I) besylate, with the results of the isolated crystal X-ray diffraction unit cell (X-ray results for ambient crystallizations unless

Observed crystallizations X-ray Solvent Co / antisolvent (& conditions) Appearance Form (N- and appearance of crystals) Methanol ethanol (at 4 °), 3 days) Plates and plates 2 (hex, plate) Ethanol ethyl acetate ( at 4 ° C, 3 days) Blades and plates 2 (4 plates) Ethanol ethyl acetate Blades and plates 2 (6 plates) Isopropyl acetate Ethanol (70 ° C -> 20 ° C) Blades, plates and needles 2 (2 plates) Isopropyl acetate Ethanol (50 ° C -> 20 ° C) Slides and plates (2 hex plates, 2 plates, 2 slides) Ethanol methyl isobutyl ketone (at 4 ° C, 3 days, silanized vial) ) tabular plates (2 (3 plates) ethanol p-cymene (at A-C, 3 days, vial plate & tabular (3 (2 tablets) silanized) nonane none (silanized vial) slides and plates 2 (plate ) dimethyl sulfoxide 1,2-chlorobenzene intercrossed slides, dendrite, one huge tabular (2 tabular) Dimethylacetamide methyl isobutyl ketone Fragments as plate 1 (slide) Dimethylacetamide tetrachlorethylene 1 intercrushed mines 1 (2 slides) acetonitrile water interface 2 (2 tabular) acetoriitrile 3-methylbutan-1-ol triangular plates, fragments and dendrite 1 (slide) acetonitrile 1,2-dichlorobenzene spherule slides 1 ( 2 blades) acetonitrile pentyl acetate bead blades 1 (plate) methanol none Plates and fragments 2 ((plate) Methanol 3-methylbutan-1-ol triangular plates and fragments 1 (2 slides) methanol methyl isobutyl ketone fragments and slides 1 (slide) 2, 2, 2-trifluoroethanol 1,2-dichlorobenzene Interface & opaque slide & translucent slides 1 (trans, slide) 2, 2, 2-trifluoroethanol 1,4-dimethylbenzene Fragments as plate 1 (sp. Plate) ethanol methyl isobutyl ketone interface plates (5 ° C: tabular & plate) 1 (interface), 2 (tabular) ethanol 1,2-dichlorobenzene interface plates (5 ° C: needles) 2 (plate) ethanol tetrachlorethylene interface (5 ° C: hexagonal tabular) 2 (slide 4 QC) ethanol 1,4-dimethylbenzene interface slides 1 (slide) propan-1-ol no fragments as plate 1 (plate) propan-1-ol 1 2-dichlorobenzene interface 1 (slide) propan-1-ol tetrachlorethylene fragments as plate & interface 1 (slide) propan-2-ol 1,2-dichlorobenzene needles & dendrite 1 (slide) propan-2-ol n-nonane slides , needles and spheroidal needles 1 (needle) 2-methoxy ethanol water slide 1 (2 blades) 2-methoxy ethanol pentyl acetate Needles 1 (blade) 2-methoxy ethanol 1,4-dimethylbenzene Blades and needles 1 (blade ) 2-methoxy ethanol n-nonane Blades and dendrite 1 (slide) Tetrahydrofuran water plate 1 (plate) Tetrahydrofuran 3-methyl butan-1-ol Intercrossed slides 1 (plate) Tetrahydrofuran 1,2-dichlorobenzene Prismatic tabular, fragments, powder 2 (3 tabular) Tetrahydrofuran ethyl acetate Dendrite, interface 2 (plate, 4 ° C) Isopropyl acetate tetrahydrofuran Intergrated plates and intergrated plates 1 (plate) Tetrahydrofuran 1,3-dimethylbenzene intercrossed slides 1 (plate) 1,4-dioxane pentyl acetate Triangular plates, some 1 (2 triple plate) of spherulite 1,4-dioxane 1,4-dimethylbenzene Slide 1 ( blade)

A variety of quality crystals suitable for determining the complete crystal structure by X-ray diffraction and the complete structure obtained for Forms 1 and 2 were achieved. These crystal structures are set forth in Examples 9 and 10.

Example 9

Shape 1 Crystal Structure

Crystals of the compound of formula (I) besylate grown from a 2-methoxyethanol: pentyl acetate solution that have a needle appearance are depicted as an image in Figure 17. An isolated needle-like crystal (about 0 ° C, 8 χ

0.04 χ 0.02 mm in size) was selected and its cell parameters determined at 260 K and then 190 K. No transition was observed in the temperature decrease between 260 - 190 Κ. The structure analyzed here is for data at 190 K; Crystal parameters and X-ray diffraction refinement are given in Table 15.

Table 15. Crystal growth data for 2-methoxyethanol: pentyl acetate of the compound of formula (!) Besylate, Form 1.

Crystal Status Code CNS7056 besylate Solvent 2-methoxyethanol Anti-solvent / Co-pentyl acetate Needle Crystal Morphology Crystal Size (mm) 0.8 χ 0.04 χ 0.02 Colorless Color Crystal Structure Formula C54H5oBr2NeOioS2 Formula Weight 1,194.98 Monocyclic System Space Group, P2i Unitary Cell a (A) 7,6868 (1) b (Á) 29,2607 (5) c (A) 12,3756 (3) α (A) 90 (3 (A) 97, 7880 (8) y (A) 90 Volume (A) 2757.86 (9) Z (No. molecules in unit) 2 Z '(No. molecules in asymmetric unit) 2 Density (g cm3) 1.439 Absorption μ [ΜοΚα] (mm 1) 1.610 F (OOO) 1224 Data Collection Temperature, (K) 190 Instrument Diffractometer Kappa CCD Test Type ω Multi-Scan Absorption Correction Type Reflection No. Measured 9868 Reflection No. Independent 9848 θ min / max (°) 1.80 / 27.49 h min / max -9/9 k min / max -37/36 I min / max -15/15 Refinement Refinement In F Range of Ι / σ 3 Number of Reflections Used 6821 Number of Parameters 686 Factor R (%) 6.34 factor Rw (%) 6.39 S 1.00 Ap (min) A "3 -0.8 Ap (max) A" 3 0.8 Max Deviation / Error 0.0005 Flack Parameter 0.027 (11)

The content of the asymmetric unit is shown in figure 18. It

It consists of two independent molecules of the compound and two independent besylate indicator ions. Each compound has protonated imidazole-nitrogen.

The "Enantiopole" Flack parameter was determined as 0.03 (1)

and thus the stereochemistry of the structures represented in this case are well established and are consistent with the proposed stereochemistry of the compound:

The crystallographic coordinates and other relevant data are

tabulated as a SHELX file in Table 17.

The conformation disorder can be represented (at first approximation) by the "thermal ellipsoids" of atomic positions, as shown in figure 19. It can be observed that the main disturbance regions are located in the methyl and besylate groups.

The difference between the two independent molecules comes mainly from the ester chains as seen in Figure 20. One molecule has the coplanar ester chain with the imidazole ring, while the other molecule has the orthogonal ester chain. The conformation of the ester chains are different from that of Form 2 (Figure 21). The orthogonal conformation observed in Form 1 has the highest similarity to that found in Form 2.

The two independent besylates have zigzag conformations (Fig. 22). No substantial differences in bond lengths are apparent.

A besylate adopts the conformation observed for the besylate in Form 2 (Fig.23).

The resolved crystal structure, observed along the crystallographic axes a, b and c, is illustrated in figure 24 a, b and c respectively. Figure 25 summarizes the shortest contacts observed in crystal compaction.

Each compound interacts with the two independent besylates. In particular, a short distance is established between an oxygen atom of a besylate and the protonated nitrogen of the imidazole ring of the compound. The second independent compound interacts similarly, but with the second independent besylate.

Other close contacts (C-O, Η-O) between the compounds and besylates are observed mainly in the vicinity of imidazole and the pyridyl ring. Some intimate contacts are also observed between the two compounds themselves (Br-N, C-C, O-H) and the two besylates themselves (O-H contacts) but to a lesser extent to the latter.

Using the experimentally determined crystal structure, a powder diffraction pattern for Form 1 was calculated using CristalDiffract® (CristaIDiffract is a Registered Trademark of CrystalMaker Ltda.) And is depicted in Fig 26. This powder standard matches the experimental powder standard reported for Form 1. Example 10

Crystalline Structure of Form 2

A crystal of the compound of formula (I) besylate Form 2, has a plaque appearance, shown in image form in Figure 27.

An isolated crystal with a plaque appearance (around 0.7 χ 0.30 χ 0.25 mm in size) was selected and its cell parameters determined at 260 K then at 190 K. No transition was observed in the decrease. temperature range between 260 - 190 Κ. The structure analyzed here is for data at 190 K; crystal parameters and X-ray diffraction refinement are given in Table 16.

Table 16. Crystal data of the compound of formula (!) Besylate. Form 2 grown in ethanol: ethyl acetate.

Crystal State

Code CNS7056 besylate Ethanol Solvent Anti-Solvent / Cosolvent Ethyl Acetate Crystal Morphology Plate Crystal Size (mm) 0.7x0.30x0.25 Color Colorless Crystal Structure Formula C27H25Bn N4O5S1 Formula Weight 597.49 Monocline System Space Group P2i2121 Unitary Cell (A) 8.92130 (10) b (A) 11.1526 (2) c (A) 25.8345 (4) a (Á) 90 P (A) 90 v (°) 90 Volume (Á) 2570, 65 (7) Z (No. of molecules in unit) 4 Z '(No. molecules in asymmetric unit) 1 Density (g cm3) 1,544 Absorption μ [ΜοΚα] (mm "1) 1,727 F (OOO) 1224 Collection Temperature Temperature, (K) 190 Instrument Diffractometer Kappa CCD Test Type ω Multi-scan Absorption Correction Type No. of Reflections Measured 5750 No. of Independent Reflections 5727 θ min / max (°) 5,15 / 27 , 48 hr min / max -11/11 k min / max -14/14 I min / max -33/33 Refinement Refinement In F IIo Range 3 No. of Reflections Used 4067 Parameter No. 344 Factor R (% ) 3.85 factor Rw (%) 3.66 S 1.12 Ap (min) A 3 -0.6 A p (max) A "3 0.5 Max Deviation / Error 0.0003 Parameter Flack 0.011 (9)

The content of the asymmetric unit is shown in figure 28.

It consists of one independent compound molecule and one independent besylate molecule. The compound has protonated imidazole nitrogen.

The "Enantiopole" Flack parameter was determined as 0.011 (9) and thus the stereochemistry of the structures represented here are well established and are consistent with the proposed stereochemistry of the compound. The crystallographic coordinates and other relevant data are shown in the form of a SHELX file in Table 18.

The conformation disorder can be represented (at first approximation) by the "thermal ellipsoids" of atomic positions, as shown in figure 29. It can be observed that the main regions of the disorder are located in the besylate.

As discussed above, the ester chain conformation in Form 2, shown in Figure 30, is different from that in Form 1.

However, the conformation of besylate is similar to that observed for one of besylate in Form 1 (Figure 31).

The resolved crystal structure observed along the crystallographic axes a, b and c is shown in Fig. 32 a, b and c respectively with Fig. 33 summarizing the shorter contacts observed in the crystal compaction. The compound establishes a short (hydrogen bond type) contact with an besylate oxygen atom through its protonated imidazole ring nitrogen. Other short contacts (C-C, C-O, Η-O) are observed between the compound and the besylate through the imidazole anol ring.

Some close contacts are also observed between the two compounds themselves (Br-C, C-C1 O-C, O-H), most of which are via the ester chain. There are no close contacts between the besylates themselves.

Some close contacts are also observed for the two compounds themselves (Br-C, C-C, O-C, O-H), most of which are via the ester chain. There are no close contacts between the besylates themselves.

Using the experimentally determined crystal structure, a powder diffraction pattern for Form 2 was calculated using Diffract® Crystal (Figure 34). This powder pattern matches the experimental powder pattern reported for Form 2.

Table 17. Crystallographic coordinates and other relevant data table in the form of a SHELX File for the compound of formula (I) besylate Form 1.

TOL Compound CNS7056 FormA 1

12161316

7,687 29,261 90,000 97,788 90,000

ZERR 2 0.0001 0.0005 0.0003 0.0008 0.0000

LATT -1

20.843S, 1.0200 10.2075 1.5886

SFAC C 2,3100

0.5687 0.8650 =

51.6512 0.21 0.0033 0.0016 1.15

0.7700 12.0110

SFACH 0.4930 10, 0.3229 26.1257 0.1402

3.1424 0.0408 = 57.7998 0.00 0.0000 0.0000 0, 06 0.3200 1.0079 SFAC 0 3, 0 4 8 5 13.2771 2.2868 5.7011 1.5463 0, 3239 0.8670 = 32.9089 0.25 0.0106 0.0060 3.25 0.7700 15.994 SFAC BR 17.1789 2.1723 5.2358 16.5796 5.6377 0.2609 3.9851 = 41.4328 2.95 -0.2901 2.4595 1000.00 1.1000 79.9040 SFAC N 12, 2126 0.00 3.1322 9.8933 2.0125 28.9975 1.1663 = 0.5826 0 0.0061 0.0033 1, 96 0.7700 14.0067 SFAC S 6, 9053 1.46 5.2034 22.2151 1.4379 0.2536 1.5863 = 56.1720 0.86 0.1246 0.1234 53.20 1.100 32.0660 UNIT 108, 100, 20, 4, 16, 4, S80 6 0.23964 0, 43139 0.09908 11.00000 0.04634 0.03299 = 0.04052 0.00002 0 .01880 -0.00340 081 3 0.16028 0.39374 0.15143 11.00000 0.06864 0.04111 = 0.05255 -0.00210 0.02801 0.00002 082 3 0.14598 0, 47435 0, 11207 11.00000 0.08099 0.03603 = 0.04614 0.00545 0.03373 -0.00236 083 3 0.42589 0, 43401 0, 12925 11.00000 0.05754 0.08564 = 0.05198 -0 .01536 0.01792 -0.00644 C84 1 0.20581 0.41866 -0.04324 11.00000 0.05949 0, 04444 = 0.02903 0.00359 0.01728 0.00704 C85 1 0.03624 0.41100 -0.09142 11.00000

06, 06649 C86

0.10092 = 0.05586 0.01088 0.01751 0.00507 1 0.00323 0.39810 -0.20187 11.00000 10

15

25

30

0.08670 0.1465 = 0.05902 -0.02096 -0.03160 -0.00004 C87 1 0.14111

0.07916 0.11651 = 0.06238 -0.01696 C88 1 0.30473

0.09246 0.09710 = 0.04155 0.00157 0.01795

C89 1 0.33456

0.05999 0.09817 = 0.07178 -0.01451 S90 6 0.68868 0.81145

0.04072 0.02869 = 0.05437 0.00158 0.00214

91 3 0.79129 0.77464 0.08025 0.03751 =

0.04867 -0.00213 -0.00954

92 3 0.52601 0.81933 0.04778 0.05360 =

0.39209 -0.25693 11.00000

0.00195 0.02481

0.39806 -0.20987 11.00000

0.02685 0.41126 -0.10133 11.00000

0.00886 0.02173

0.51625 11.00000

0.00223

0.57315 11.00000

0.01626

0.56122 11.00000

0.06934 -0.00642

0.01702 0.00039

93 3 0.78935 0.85213

0.07515 0.04369

0.05025 -0.01354

C94

0.04232 0.05049 C95

0.06194 0.03238 C96

0.12417

1 0.62446 0.78970 0.04028

0.50763 11.00000

0.01764 -0.01547

0.38130 11.00000

0.00898 0.00929 0.00525

1 0.74659 0.76959 0.06998 =

0.32396 11.00000

1 0.69911 0.75023 0.10337 =

0.00341 -0.00103 0.00990

0.22476 11.00000 10

15

0.03441 0.01537

C97 1 0.51941 0.75295

0.11897 0.11939 =

0.02308 -0.01324 -0.00963 -0.00586

C98 0.06106

0.05463

C99

0.05307 0.04982 BRl

0.04153 0.07369 C2

0.02832

1 0.40301 0.77268 0.10242 =

1 0.45446 0.79193 0.07089 =

4 0.06011 0.52462 0.05204 = -0.00524

0.03350 -0.00752

0.02421, 0.03314

0.17732 11.00000

0.23169 11.00000

0.00570 -0.01263 -0.00283 0.33547 11.00000

0.00728 -0.00426 -0.01944 0.55140 11.00000

0.02434 0.00670

1 0.25757 0.50395 0.04536 =

0.49005 11.00000

0.01511 0.00763

C3 1 0.288921 0.45781

0.03135 0.03107 =

0.47911 11.00000

0.04579

0.00145

0.00221 -0.00479

C4 1 0.42954 0.44393 0.43174 11.00000 0.03767 0.03461 =

0.02980 -0.00320 -0.00151 -0.00125

C5 1 0.54674 0.47556 0.39943 11.00000 0.03535 0.02939 =

0.03479 -0.00390 0.00647 0.00183

C6 1 0.51907 0.52242 0.41134 11.00000 0.04226 0.03479

0.04333 -0.00172 0.00236 0.00188

C7 1 0.37213 0.53602 0.45794 11.00000 0.03598 0.02793 = 0.04586-0.00044

C8 1 0.64321 0.55824

0.03964 0.02453 =

0.02719 0.00516 0.00457

C9 1 0.68998 0.59645

0.03743 0.03694 =

0.04454 -0.00375

N0 5 0.69097 0.58514

0.06070 0.03116 =

0.04918 -0.00640

Cll, 0.74090 0.61847

0.06804 0.05787

0.04752 -0.00600

C12 1 0.78515 0.66221

0.05480 0.04458 =

0.05526 -0.02125

013 1 0.77550 0.67229

0.04463 0.03102 =

0.05452 0.00407

C14 1 0.73186 0.63955

0.04272 0.03021 =

0.04282 -0.00243

N15 5 0.71451 0.55972

0.04979 0.02502 =

0.03692 0.00975 0.01748

C16 1 0.67500 0.52204

0.04463 0.02346 =

0.04948 -0.00464

C17 1 0.75857 0.47996

0.04549 0.02673 =

0.01954 -0.00693

0.01652 0.00336

0.38118 11.00000

0.00373

0.46059 11.00000

0.01588 0.00649

0.56581 '11.00000

0.02020 -0,00054

0.63822 11.00000

0.01695 -0.00669

0.61053 11.00000

0.01554 -0.00787

0.50132 11.00000

0.01432 -0,00038

0.42553 11.00000

0.01499 0.00270

0.29408 11.00000

0.00775

0.21324 11.00000

0.01738 0.00561

0.26673 11.00000

0.00506 -0.00121 N18

0.03293

C19 0.03678

C20

0.03371

Ν21

0.04775 C22

0.03997 0.04548 C23

0.05650 0.03514 C24

0.08242 0.03001 C25

0.06429 0.03392 026 0.12347 0.04188 027

0.10340 0.03191 C28

0.70009 0.455973 0.35517 11.00000

0.02806 =

0.02597 -0,00088 0.00321 0.00207

1 0.81334 0.42409 0.39181 11.00000

0.02848 =

0.03351 -0.00426 0.00585 0.00488

1, 0.93968 0.42402 0.32661 11.00000

0.02802 =

0.03711 0.00202 0.00106 0.00680

0.90585 0.455925 0.251515 11.00000

0.03416 = 0.02231 -0.01051 0.01052 -0.00308

1 0.79597 0.39511 0.48941 11.00000

0.03711 =

0.01039 0.00508 0.00197 1 0.744788 0.53407 0.10940 11.00000

0.04712 =

0.00836 0.00449 0.00605 1 0.68780 0.50047 0.01647 11.00000

0.04077 =

■ 0.00046 0.01385 0.00523

1 0.71419 0.51690 -0.09234 11.00000

0.06543 =

0.00018 3 0.76261 0.08282 =

0.01501 3 0.65910 0.06919 =

0.00253 1 0.66642

0.00559 -0.00499 0.55440 -0.11450 11.00000

0.01658 -0.04001 0.48459 -0.16756 11.00000

0.01824 -0.00449 0.499760 -0.27953 11.00000 0.19131 0.01390 BR51 0.03812 0.06774 C52

0.03132 0.03819 C53 0.04627 0.03723 C54

0.04551 0.04858 C55

0.04294 0.03413 C56 0.02688 0.04586 C57

0.03105 0.04447 C58 0.03348 0.04334 C59

0.03165 0.04951

0.12699 =

-0.01417

4 1.06737 0.08781 =

0.00566 1 0.84276 0.05952 =

0.00358 1 0.81293 0.06820 =

-0.00581

1 0.65043 0.03939 =

-0,00084

1 0.51946 0.03573 =

0.00062 1 0.54512 0.03659 =

0.00025

1 0.71139 0.04840 =

0.00668 -0.00429

1 0.40956 0.02893 =

0.00070 1 0.38048 0.03488 =

0.00002

0.71057

■ 0.00531 0.73306

0.77906

0.79579

0.76552

0.71765

0.00561 0.70186

0.68443

0.00351 0.64253

0.02134 -0.05279 0.98743 11.00000

0.00447

0.93243 11.00000

0.00226 -0.00263 0.93249 11.00000

0.00481 -0.00474 0.88269 11.00000

0.00376 -0.01071 0.84226 11.00000

0.00952 -0.00208 0.84581 11.00000

0.00047

0.898914 11.00000

0.00504

0.79765 11.00000

0.00421

0.86694 11.00000

0.00425 0.00528 Ν60 5 0.42879 0.644650

0.03542 0.05694 =

0.03178 0.00872 0.00154 0.00467

0.97247 11.00000

C61 0.04457

C62

0.06548

C63

0.07395

C64

0.08355

15

Ν65

0.03846

C66 0.03574

C67

0.03803

Ν68

0.03387

C69

0.05345

1 0.38962

0.06338 =

0.05765 0.01416

1 0.30187

0.04957 =

0.11303 0.03456

1 0.25733

0.04664 =

0.09803 0.00115

1 0.29561

0.04152 =

0.05459

0.31344

0.03072 =

0.04952

1 0.33129 0.02676 =

0.05519 0.00406

1 0.26347 0.03316 =

0.04166 0.01528

0.35122

0.03259 =

0.05055 0.00549

1 0.24763 0.03305 =

0.61026

0.00707 0.57202

0.03582 0.56863

1.03529, 11.00000

0.60475

-0,00010 0.68797

-0.00160 0.72953

0.00580 0.76733

0.00868 0.78274

0.00427 0.81583

0.00171

0.98967 11.00000

0.00696

0.88018 11.00000

0.01240 -0.01007

0.81590 11.00000

0.00128 -0.02308

0.70771 11.00000

0.00032 0.00597

0.64125 11.00000

0.00330

0.70231 11.00000

0.00029

0.79764 11.00000

0.00218

0.84108 11.00000 10

C70

0.04465

Ν71

0.03892

C72

0.08091

C73

0.04039

C74 0.05896

C75

0.05296

076

0.05552

077

0.08466

25

C78

0.06302

0.04570 0.00005

1 0.09873 0.81841 0.03799 =

0.02067 -0.00546

0.77077 11.00000

0.06107 0.00794 0.01464 0.00936

0.10819 0.78841 0.03266 =

0.05306 0.00974 0.01063 0.00803

1 0.30218 0.84064 0.04934 =

0.688720 11.00000

0.94469 11.00000

0.08052 -0.01505

1 0.22541 0.72388 0.05583 =

0.03295 0.00047

1 0.30154 0.68566 0.05343 =

0.05504 -0.00576

1 0.18003 0.67204 0.05447 =

0.02392 -0.00661

0.52948 11.00000

0.00724 -0.00165

0.46508 11.00000

0.00667 0.02016

0.36587 11.00000

0.04241 0.00546 0.01355 0.00171

3 0.06782 0.69497 0.31818 11.00000 0.07543 =

0.05719 -0.00702 -0.00194 0.02108

3 0.22119 0.62976 0.33149 11.00000 0.04267 =

0.04376 -0.00714 0.00726 0.00488

1 0.10717 0.61220 0.23887 11.00000 0.09312 =

0.07465 -0.02449 0.02418 -0.00980

611 2 10.42342 10.61111 11.10933 11.00000 0.06582

621 2 10.27371 10.54835 11.03412 11.00000 0.09086

31631 2 10,20282 10,54235 10,84949 11.00000 0.08585 Η641 2 10,26600 10.60396 10.744163 11.00000 0.07058 Η661 2 10.45616 10.73494, 10.63683 11.00000 0 , 04658 Η701 2 10,00528 10,83765 10,77749 11,00000 0,05724 Η721 2 10,20390 10,85662 10,96784 11,00000 0,10482 Η722 2 10,39143 10,86277 10,93477 11,00000 0.10500 Η723 2 10.34863 10.81975 11.00178 11.00000 0.1079 Η731 2 10.22647 10.75279 10.49048 11.00000 0.05050 Η732 2 10.10462 10.71635 10.53573 11, 00000 0.05107 Η741 2 10.41143 10.69632 10.444327 11.00000 0.06599 Η742 2 10.32279 10.65905 10.51273 11.00000 0.06616 Η571 2 10.73613 10.67093 10.88928 11 .00000 0.04893 Η531 2 10.89874 10.799871 10.96543 11.00000 0.05990 Η541 2 10.63029 10.82681 10.87790 11.00000 0.05285 H1 61 2 10.54702 10.51731 10, 19609 11.00000 0.04687 Η201 2 11.03302 10.40374 10.33036 11.00000 0.03977 Η221 2 10.90306 10.37871 10.51025 11.00000 0.06107 Η222 2 10.77134, 10.41394 10.5 4853 11.00000 0.06102 Η223 2 10.70245 10.377370 10.47387 11.00000 0.06087 Η231 2 10.71028 10.56434 10.08666 11.00000 0.05487 Η232 2 10.87494 10.53365 10 , 12431 11.00000 0.05471 Η241 2 10.56546 10.49241 10.01723 11.00000 0.06095 Η242 2 10.75795 10.47323 10.02815 11.00000 0.06099 H111 2 10.74728 10.61186 10.71244 11.00000 0.06882 Η121 2 10.81997 10.68398 10.66349 11.00000 0.06182 H1 31 2 10.79812 10.70154 10.48020 11.00000 0.05215 H1 41 2 10.72939 10.64544 10.35226 11.00000 0.04595 Η71 2 10.35042 10.56684 10.46668 11.00000

0.04408 H31 2 10.21444 10.43638 10.50355 11.00000 0.04223 H41 2 10.44931 10.41280 10.42055 11.00000 0.04056 H891 2 10.44977 10.41481 9.93226 11, 00000 0,09285 H881 2 10,39917 10,39332 9,75106 11,00000 0,09266 H871 2 10,12372 10,38356 9,66972 11,00000 0,10194 H861 2 9,88808 10,39388 9,76390 11 0.00000 0.1607 H851 2 9.94416 10.41466 9.94909 11.00000 0.08904 H951 2 10.86472 10.76918 10.355546 11.00000 0.06580 H961 2 10.788321 10.73544 10.18942 11.00000 0.10497 H971 2 10.48493 10.74055 10.10914 11.00000 0.10604 H981 2 10.28646 10.737378 10.20054 11.00000 0.08719 H991 2 10.337377 10.80653 10, 37249 11.00000 0.07037 H781 2 10.14480 10.58182 10.22240 11.00000 0.11588 H782 2 10.11102 10.63197 10.17669 11.00000 0.11581 H783 2 9.98883 10.61082 10 , 25546 11.00000 0.1600 H711 2 10.01359 10.788308 10.62464 11.00000 0.05205 H211 2 10.98261 10.46785 10.19729 11.00000 0.04161 H281 2 10.62358 10.47180 9.67092 11.00000 0.11 566 H282 2 10.59036 10.52501 9.70225 11.00000 0.11566 H283 2 10.79029 10.50514 9.71088 11.00000

0.11566

Table 18. Crystallographic coordinates and other relevant data tabulated in the form of a SHELX File for the compound of formula (I) besylate Form 2.

TlTL 1 142055 Compound CNS7056 Form 2

CELL 0.71073 8.921 1 1, 1 54 25.834 90,000 90,000 90,000 ZER R 4 0.0001 0.0002 0.0004 0.0000 0.0000 0.0000 LATT -1

SYMM X + 0.500, -Y + 0.500, -Z

SYMM -X, Y + 0.500, -Z + 0.500, SYMM -Χ + 0.500, -Υ, Ζ + 0.500

SFAC C

0.5687 0.8650 =

51, 6512 0.7700 12.01 1 0

SFAC H

3.1424 0.0408 =

57.7998

0.3200 1.0079

SFAC BR 17.1789

0.2609 3.9851 =

41, 4328 1,1000 79.9040

SFAC N 28.9975

12.2126 1,1663 =

0.7700 14.0067 SFAC 0

20

0.3239 0.8670 =

32.9089 0.7700 15.9994

SFAC S 6,9053

0.2536 1.5863 =

56.1720 1.1 100 32.0660

2.3100 20.84391.0200 10.20751.5886

0.2156 0.0033 0.0016 1.15

0.4930 10.51090.3229 26.1257 0.1402

0.0030 0.0000 0.0000

0.06

2.1 723

5.2358 16.5796 5.6377

2,9557 -0,29012,4595 1000.00 0.0057 3,1322 9.8933 2.0125

0.5826 -1 1, 5290 1.96

3.0485 1 3.2771 1.5463

0.0061 0.0033

2,2868 5,701 1

0.2508 0.0106 0.0060 3.25

1.4679 5.2034 22.2151 1.4379

0.8669 0.1246 0.1234

53.20

UNIT 108, 100, 4, 16, 20 4,

BR1 3 -0.0481 9 -0.10880 -0.27710 11.00000

0.07032 0.03277 =

0.03090 0.00144 -0.01238 -0.02224

C2 1 -0.15018 -0.21830 -0.32054 1 1.00000 0.02777 0.02177 =

0.02345 -0.00009 -0.00209 -0.00471

C3 1 -0.17401 -0.18875 -0.37205 1 1.00000

0.02963 0.01861

0.02702 0.00623 0.00188 -0.00107

C4 1 -0.24491 -0.26965 -0.40362 11.00000

0.02825 0.02442 =

0.01718 0.00327 0.00106 -0.00145

C5 1 -0.29275 -0.37943 -0.38401 1 1.00000

0.02223 0.01822 =

0.01875 -0,00067 0.00141 0.00066

C6 1 -0.271 39 -0.40894 -0.33163 1 1.00000

0.02028 0.01967 = 0.019260.00182 0.00105 -0.00153

C7 1 -0.20042 -0.32532 -0.29979 11.00000

0.02809 0.02763 =

0.01685 0.00206 0.00190 -0.00055

C8 1 -0.32197 -0.52600 -0.30927 11.00000

0.01670 0.02233 =

0.01945 0.00135 -0.00476 -0.00144

C9 1 -0.39853 -0.52353 -0.255770 11.00000

0.01623 0.02317 =

0.01584 0.00259 -0.00384 -0.00281

N10 4 -0.46099 -0.41943 -0.24363 11.00000

0.02251 0.02613 =

0.02353 -0.00189 0.00408 0.00155

C11 1 -0.52777 -0.41652 -0.19697 11.00000

0.02617 0.03441 =

0.02357 -0.00451 0.00365 0.00346

C12 1 -0.53610 -0.51390 -0.16425 11.00000

0.02740 0.04329 = 0.02040 -0.00335 0.00652 -0.00779

C13 1 -0.47518 -0.62062 -0.17997 11.00000

0.03584 0.03200

0.02405 0.00767 0.00645 -0.00687

C14 1 -0.40334 -0.62685 -0.22730 11.00000

0.02879 0.02223 =

0.02565 0.00090 0.00272 -0.00057

415 4 -0.30040 -0.62781 -0.33049 11.00000

0.02151 0.02416 =

0.01713 0.00287 -0.00002 0.00182

C16 1 -0.21928 -0.62991 -0.38036 11.00000

0.02330 0.02286 =

0.01602 0.00057 0.00417 0.00450

C17 1 -0.32510 -0.57975 -0.41920 11.00000

0.02824 0.02308 =

0.01704 -0.00121 0.00336 -0.00285,

418 4 -0.36294 -0.46298 -0.41818 11.00000

0.02482 0.02037 =

0.01483 0.00150 -0,00070 0.00079

C19 1 -0.46920 -0.44117 -0.45641 11.00000

0.03022 0.02725 =

0.01634 0.00325 0.00039 -0.00224

C20 1 -0.49445 -0.54753 -0.47911 11.00000

0.03071 0.03401 =

0.01669 0.00110 -0.00174 -0.00215

421 4 -0,40440 -0,63226 -0,45591 11.00000

0.03619 0.02354 =

0.02146 -0.00463 0.00147 -0.00154

C22 1 -0.54310 -0.32298-0.46595 11.00000

0.03636 0.03429 =

0.03074 0.00778 -0.00982 -0.00011

C23 1 -0.15995 -0.755547 -0.39193 11.00000 0.03430 0.02640 =

0.01793 -0.00359

0.00177 0.00554

10

15

20

25

30

C24

0.04707 C25

0.03182

26

0.03778

27

0.03130

C28

0.05622 S80

0.03340

81

0.05118

82

0.04015

1 -0.06166 -0.79435 -0.364621 11.00000

0.03881 =

0.02350 0.00041 0.00034 0.01530

1 0.06625 -0.87542 -0.35603 11.00000

0.02650 =

0.01948 0.00340 -0.00125 -0.00016

0.17233 -0.88334 -0.33760, 11.00000

0.06570 =

0.03313 -0.01160 -0.01173 0.00417

0.05245 -0.94265 -0.39885 11.00000

0.03874 =

0.02467 -0.00799 -0.00330 0.01418

1 0.17574 -1.02443, -0.40865 11.00000

0.08123 =

0.03697 -0.01153 -0.00496 0.04396

6 -0,94275 -0,52899 -0,49624 11.00000

0.02679 =

0.02442 0.00000 0.00210 -0.00075

-0.83867 -0.47114 -0.53020 11.00000 0.08336

0.03575

0.02297 -0.00622 -0.02476

0,

05 2 50 3-2 0, 01 2 02 2 - 0,

-1.08156 -0.46260 -0.49186 11.00000 0.07788 =

9,33331 9,33306 9,06867 9,64846

9.17563 9, 67239

9.65289 11.00000 9.57936 11.00000 9.66111 11.00000 10

15

20

83

0.13945

C84

0.02735

C85

0.03763

C86

0.05438

C87 0.06202

C88

0.04217

C89

0.03725

Η891

00539

-0.97025 -0.65272 -0.50726 0.03230 =

0.06071 -0.01467

1 -0.86288 -0.52210 -0.43343 0.05893 =

0.02832

0.01509

1 -0,87781 -0,41462 -0,40588 0.08695

0.03855 -0.01799

1 -0.81420 -0.39965 -0.355764 0.16315 =

0.04455 -0.02905

1 -0.73766 -0.49241 -0.33773 0.20226 =

0.06481

1 -0.71885 -0.60444 -0.36221 0.17120 =

0.11388

1 -0.78500 -0.61610-0.41251 0.08786 =

0.07642

2 9,22557

9.31210

0.01721 11.00000

0.01447 -0.00725 11.00000

0.00686 -0.00534 11.00000

0.00427 -0.00754 11.00000

0.00147 -0.02905 11.00000

0.03510 -0.02105 -0.05062 11.00000

0.10762 -0.01320 -0.03729 11.00000

0.05538 -0.00772 -0.01074 9.56883 11.00000 0.08027

Η881 0.13097 Η851 0.06577 Η861 0.10509 H1 61 2 9.86530 9.42517 9.62245 11.00000 0.02469 H111 2 9.42959 9.65626 9.81326 11.00000 0.03383 Η121 2 9 , 41618 9.49292 9.86839 11.00000 0.03606 H1 31 2 9.51614 9.31066 9.84059 11.00000 0.03697 Η141 2 9.64103 9.30191 9.761414 11.00000 0.03108 Η231 2 9.89972 9.24922 9.57680 11.00000 0.03066 Η232 2 9.75764 9.18723 9.60372 11.00000 0.03099 Η241 2 9.87585 9.166237 9.67759 11.00000 0.04434 H242 2 9.97980 9.27746 9.67100 11.00000 0.04489 H281 2 10.15353 8.92912 9.56085 11.00000 0.08666 H282 2 10.18989 8.92278 9.62053 11.00000 0, 08723 H283 2 10.26566 9.02166 9.58620 11.00000 0.08710 H201 2 9.44027 9.43682 9.49457 11.00000 0.03327 H221 2 9.36727 9.66624 9.51370 11.00000 0 . 05146 H222 2 9.52479 9.72860 9.51527 11.00000 0.05104 H223 2 9.43163 9.71611 9.56601 11.00000 0.05131 H41 2 9.73983 9.74902 9.56204 11.00000 0.02807 H31 2 9.85823 9.88568 9.61518 11.00000 0.03001 H71 2 9.81367 9.65791 9.73490 11.00000 0.02870 H871 2 9.30621 9.51762 9.69480 11.00000 0.13226 H211 2 9.59801 9.29339 9.53630 11, 00000 0.03270

Table 19. Binding lengths for the compound of formula (I) besylate Form 1.

S80 081 1.444 (5) A S80 083 1.432 (6) A C84 C85 1.376 (12) A C85 C86 1.408 (14) A C86 C87 1.360 (16) A C87 C88 1.310 (15) A C88 C89 1.386 (14) A C89 H891 0.932A S90 092 1.444 (6) At S 90 C94 1.793 (8) At C94 C99 1.354 (11) AC 95 H951 0.938À C96 H961 0.934À

S80 082 1.468 (5) A S80 C84 1.784 (7) A C84 C89 1.318 (12) A C85 H851 0.927A C86 H861 0.936A C87 H871 0.934A C88 H881 0.935Á S90 091 1.459 (5) A S90 093 1.431 (5) A C94 C95 1.383 (11) A C95 C96 1.356 (13) A C96 C97 1.428 (17) A C97 C98 1.323 (15) A C97 H971 0.924A C98 H981 0.927A Brl C2 1.886 (6) To C2 C7 1.381 (9) A C3 H31 0.928A C4 H41 0.937Á C5 N18 1.444 (8) À C6 C8 1.498 (9) À C8 C9 1.500 (9) Á C9 N10 1.343 (9) à N10 C11 1.345 (10) A C11 H111 0.933Á C12 H121 0.927À C13 H131 0.918À N15 C16 1.492 (9) Á C16 C23 1.511 (9) Á C17 N18 1.352 (8) À N18 C19 1.400 (8) Á C19 C22 1.496 (9) Á C20 H201 0.927À C22 H221 0.958À C22 H223 0.953A C23 H231 0.962À C24 C25 1.470 (11) A C24 H242 0.962A C25 027 1.354 (10) A C28 H281 1,000A C28 H283 1,000A

C98 C99 1.409 (13) A C99 H991 0.924A C2 C3 1.382 (9) A C3 C4 1.358 (10) A C4 C5 1.388 (9) A C6 C7 1.394 (9) A C7 H71 0.926A C8 N15 1.274 (8) A C9 C14 1.386 (9) A C11 C12 1.379 (11) A C12 C13 1.375 (11) A C13 C14 1.351 (10) A C14 H141 0.921 A C16 C17 1.500 (9) A C16 H161 0.988A C17 N21 1.315 (8) A C19 C20 1.344 (9) A C20 N21 1.376 (8) A N21 H211 1.000A C22 H222 0.950A C23 C24 1.536 (11) A C23 H232 0.969Á C24 H241 0.971 A C25 026 1.202 (10) A 027 C28 1.445 (10) A C28 H282 1, OOOA Br51 C52 1.886 (7) A C52 C53 1.366 (11) A C53 C54 1.404 (11) A C54 C55 1.383 (10) A C55 C56 1.414 (9) A C56 C57 1.396 (9) A C57 H571 0.925A C58 N65 1.254 (8) A C59 C64 1.391 (10) A C61 C62 1.386 (14) A C62 C63 1.355 (15) A C63 C64 1.378 (13) A C64 H641 0.917Á C66 C67 1.474 (9) A C66 H661 0.982 A C67 N71 1.334 (8) A C69 C70 1.343 (11) A C70 N71 1.366 (10) A N71 H711 1, OOOA C72 H722 0.958A C73 C74 1.535 (10) A C73 H 732 0.967 A C74 H741 0.972A C75 076 1.185 (9) A 077 C78 1.440 (11) A C78 H782 0.966À

C52 C57 1.412 (10) A C53 H531 0.927 A C54 H541 0.921 A C55 N68 1.427 (9) A C56 C58 1.489 (9) A C58 C59 1.530 (10) A C59 N60 1.314 (9) A N60 C61 1.372 (10) A C61 H611 0.918Á C62 H621 0.928À C63 H631 0.932À N65 C66 1.485 (8) A C66 C73 1.516 (10) A C67 N68 1.344 (9) N68 C69 1.406 (9) A C69 C72 1.484 (12) A C70 H701 0.925 A C72 H721 0.964Á C72 H723 0.965Á C73 H731 0.975À C74 C75 1.493 (12) A C74 H742 0.977À C75 077 1.360 (9) To C78 H781 0.965À C78 H783 0.960Á

Table 20. Angles for the compound of formula (I) besylate Form 1

081 S80 082 111.0 (3) ° 082 S80 083 114.4 (4) °

081 S80 083 112.9 (4) ° 081 S80 C84 105.5 (3) ° 082 S80 C84 106.2 (3) ° S80 C84 C85 117.7 (6) ° C85 C84 C89 118.3 (8) ° C84 C85 H851 119.626 ° C85 C86 C87 118.1 (10) ° C87 C86 H861 121.303 ° C86 C87 H871 119.251 ° C87 C88 C89 119.3 (10) ° C89 C88 H881 120.264 ° C84 C89 H891 118.485 ° 091 S90 092 111, 7 (3) ° 092 S90 093 113.5 (3) ° 092 S90 C94 105.7 (3) ° S90 C94 C95 120.6 (6) ° C95 C94 C99 119.3 (8) ° C94 C95 H951 118.566 ° C95 C96 C97 118.4 (10) ° C97 C96 H961 121.695 ° C96 C97 H971 119.699 ° C97 C98 C99 120.8 (9) ° C99 C98 H981 120.094 ° C94 C99 H 991 119.276 ° Br1 C2 C3 121.0 (5) ° C3 C2 C7 120.5 (5) ° C2 C3 H31 120.203 ° C3 C4 C5 120.6 (6) ° C5 C4 H41 118.766 ° C4 C5 N18 119.6 (5) °

083 S80 C84 106.0 (4) ° S80 C84 C89 123.6 (7) ° C84 C85 C86 120.0 (9) ° C86 C85 H851 120.377 ° C85 C86 H861 120.636 ° C86 C87 C88 121.8 (10) ° C88 C87 H871 118.984 ° C87 C88 H881 120.392 ° C84 C89 C88 122.5 (10) ° C88 C89 H891 119.061 ° 091 S90 093 112.8 (4) ° 091 S90 C94 104.5 (3) ° 093 S90 C94 108, 0 (3) ° S90 C94 C99 120.1 (6) ° C94 C95 C96 121.6 (9) ° C96 C95 H951 119.820 ° C95 C96 H961 119.911 ° C96 C97 C98 119.9 (8) ° C98 C97 H971 120.397 ° C97 C98 H981 119.080 ° C94 C99 C98 119.9 (9) ° C98 C99 H991 120.819 ° Br1 C2 C7 118.5 (5) ° C2 C3 C4 119.7 (6) ° C4 C3 H31 120.109 ° C3 C4 H41 120.600 ° C4 C5 C6 120.6 (6) ° C6 C5 N18 119.8 (6) ° C5 C6 C7 117.8 (6) ° C7 C6 C8 118.8 (6) ° C2 C7 H71 119.721 ° C6 C8 C9 117, 5 (5) ° C9 C8 N15 115.9 (6) ° C8 C9 C14 121.2 (6) ° C9 N10 C11 115.5 (6) ° N10 C11 H111 118.526 ° C11 C12 C13 117.4 (7) ° C13 C12 H121 121.289 ° C12 C13 H131 119.499 ° C9 C14 C13 118.3 (6) ° C13 C14 H141 121.419 ° N15 C16 C17 105.9 (5) ° C17 C16 C23 112.4 (5) ° C17 C16 H161 109.539 ° C16 C17 N18 122, 7 (6) ° N18 C17 N21 106.5 (5) ° C5 N18 C19 127.0 (5) ° N18 C19 C20 105.2 (5) ° C20 C19 C22 129.4 (6) ° C19 C20 H201 126.017 ° C17 N21 C20 110.5 (5) ° C20 N21 H211 124.681 ° C19 C22 H222 109.778 ° C19 C22 H223 110.905 ° H222 C22 H223 109.018 ° C16 C23 H231 109.3992 °

C5 C6 C8 123.3 (6) ° C2 C7 C6 120.6 (6) ° C6 C7 H71 119.679 ° C6 C8 N15 126.6 (6) ° C8 C9 N10 114.9 (6) ° N10 C9 C14 123, 9 (6) ° C 10 C 11 C 12 124.4 (7) ° C 12 C 11 H 11 1 117.061 ° C 11 C 12 H 12 1 121.279 ° C 12 C 13 C 14 120.4 (6) ° C 14 C 13 H 13 120 120.25 ° C 9 C 14 H 14 120 120 ° C 8 N 15 C 16 118, (5) ° N15 C16 C23 109.4 (5) ° N15 C16 H161 110.723 ° C23 C16 H161 108.851 ° C16 C17 N21 130.3 (6) ° C5 N18 C17 123.1 (5) ° C17 N18 C19 109, 8 (5) ° N18 C19 C22 125.3 (6) ° C19 C20 N21 108.0 (5) ° N21 C20 H201 126.026 ° C17 N21 H211 124.840 ° C19 C22 H221 109.508 ° H221 C22 H 222 108.808 H221 C22 H223 108.786 ° C16 C23 C24 112.3 (6) ° C24 C23 H231 108.812 ° C16 C23 H 232 108.378 ° Η231 C23 H 232 108.825 ° C23 C24 H241 109.968 ° C23 C24 H242 108.195 ° Η241 C24 H242 108.752 ° C24 C25 027 109.4 ( 7) ° C 25 027 C28 115.2 (7) ° 027 C28 H282 109.261 ° 027 C28 H283 109.465 ° Η282 C28 H283 109.476 ° Br51 C52 C57 119.0 (5) ° C52 C53 C54 118.9 (7) ° C54 C53 H531 120.985 ° C53 C54 H541 120.227 ° C54 C55 C56 122.1 (6) ° C56 C55 N68 118.5 (6) ° C55 C56 C58 123.2 (6) ° C52 C57 C56 120.2 (7) ° C56 C57 H571 120.138 ° C56 C58 N65 126.7 (6) ° C58 C59 N60 116.3 (6 ) ° N60 C59 C64 125.0 (7) ° N60 C61 C62 121.7 (8) ° C62 C61 H611 118.993 ° C61 C62 H621 120.029 ° C62 C63 C64 118.4 (9) ° C64 C63 H631 121.124 ° C59 C64 H641 120,844 °

C24 C23 H232 109.105 ° C23 C24 C25 114.3 (7) ° C25 C24 H241 110.030 ° C25 C24 H242 105.366 ° C24 C25 026 126.4 (7) ° 026 C25 027 123.9 (7) ° 027 C28 H281 109.674 ° H281 C28 H282 109.475 ° H281 C28 H283 109.476 ° Br51 C52 C53 119.3 (6) ° C53 C52 C57 121.7 (7) ° C52 C53 H531 120.141 ° C53 C54 C55 119.8 (7) ° C55 C54 H541 120.000 ° C54 C55 N68 119.4 (6) ° C55 C56 C57 117.2 (6) ° C57 C56 C58 119.5 (6) ° C52 C57 H571 119.709 ° C56 C58 C59 116.5 (6) ° C59 C58 N65 116, 8 (6) ° C58 C59 C64 118.5 (7) ° C59 N60 C61 116.1 (7) ° N60 C61 H611 119.372 ° C61 C62 C63 120.6 (8) ° C63 C62 H621 119.353 ° C62 C63 H631 120.452 ° C59 C64 C63 118.1 (8) ° C63 C64 H641 121.057 ° C58 N65 C66 118.2 (6) ° N65 C66 C73 109.7 (5) ° N65 C66 H661 109.122 ° C73 C66 H661 112.017 ° C66 C67 N71 130, 3 (7) ° C55 N68 C67 122.5 (6) ° C67 N68 C69 108.7 (6) ° N68 C69 C72 124.0 (7) ° C69 C70 N71 109.1 (6) ° N71 C70 H701 125.502 ° C67 N71 H711 125.400 ° C69 C72 H721 110.667 ° H721 C72 H 722 108.539 ° H721 C72 H723 108.455 ° C66 C73 C74 111.0 (6) ° C 74 C73 H731 110.248 ° C74 C73 H 732 108.249 ° C73 C74 C75 112.4 (6) ° C75 C74 H741 109.125 ° C75 C74 H 742 108.578 ° C74 C75 076 126.2 (7) ° 076 C75 077 123.0 (7 ) ° 077 C78 H781 109.214 ° H781 C78 H 782 109.923 ° H781 C78 H783 109.026 °

N65 C66 C67 105.4 (5) ° C67 C66 C73 111.5 (6) ° C67 C66 H661 108.890 ° C66 C67 N68 121.8 (6) ° N68 C67 N71 107.4 (6) ° C55 N68 C69 128, 7 (6) ° N68 C69 C70 105.5 (6) ° C70 C69 C72 130.5 (7) ° C69 C70 H701 125.444 ° C67 N71 C70 109.2 (6) ° C70 N71 H711 125.366 ° C69 C72 H 722 109.838 ° C69 C72 H723 110.831 ° H 722 C72 H723 108.445 ° C66 C73 H731 108.535 ° C66 C73 H 732 110.751 ° H731 C73 H732 108.042 ° C73 C74 H741 108.455 H741 C74 H 742 110.035 ° C74 C74 (7) ° C75 077 C78 115.6 (7) ° 077 C78 H782 109.848 ° 077 C78 H783 109.687 ° H 782 C78 H783 109.127 °

Table 21. Binding lengths for the compound of formula (I) besylate Form 2.

Br1 C2 1.892 (3) A C2 C7 1.383 (5) A

C2 C3 1.387 (5) À C3 C4 1.371 (5) Ã C3 H31 0.938A C4 H41 0.921À C5 N18 1.428 (4) À C6 C8 1.497 (4) Á C8 C9 1.497 (4) À C9 N10 1.338 (4) A N10 C11 1.345 (4) to C11 H111 0.935À C12 H121 0.948A C13 H131 0.936À N15 C16 1.478 (4) to C16 C23 1.527 (5) to C17 N18 1.346 (4) to N18 C19 1.391 (4) to C19 C22 1.494 (5) At C20 H201 0.912A C22 H221 0.965À C22 H223 0.960Á C23 H231 0.969À C24 C25 1.478 (5) To C24 H242 0.988Á C25 027 1.342 (4) Á C28 H281 0.964À C28 H283 0.962À S80 082 1.447 ( 3) A S80 C84 1.774 (4) A C84 C89 1.369 (7) C85 H851 0.932À

C4 C5 1.392 (5) A C5 C6 1.406 (4) A C6 C7 1.395 (5) A C7 H71 0.924 A C8 N15 1.276 (4) A C9 C14 1.395 (5) A C11 C12 1.378 (5) A C12 C13 1.370 ( 5) A C13 C14 1.382 (5) A C14 H141 0.934À C16 C17 1.487 (5) A C16 H161 0.976À C17 N21 1.320 (4) A C19 C20 1.342 (5) A C20 N21 1.378 (5) N21 H211 0.854A C22 H222 0.966À C23 C24 1.534 (5) A C23 H232 0.981Á C24 H241 0.960À C25 026 1.201 (4) A 027 C28 1.401 (5) A C28 H282 0.965A S80 081 1.431 (3) Á S80 083 1.430 (3) A C84 C85 1.400 (7) A C85 C86 1.380 (7) A C86 C87 1.342 (13) A C86 H861 0.943A C87 H871 0.934A C88 H881 0.925A

C87 C88 1.410 (13) A C88 C89 1.433 (10) A C89 H891 0.940A

Table 22. Angles for the compound of formula (I) besylate Form 2.

Br1 C2 C3 119.3 (3) ° C3 C2 C7 121.8 (3) ° C2 C3 H31 120.033 ° C3 C4 C5 120.3 (3) ° C5 C4 H41 120.261 ° C4 N5 118.9 (3) ° C5 C6 C7 118.2 (3) ° C7 C6 C8 119.5 (3) ° C2 C7 H71 120.432 ° C6 C8 C9 117.7 (3) ° C9 C8 N15 117.9 (3) ° C8 C9 C14 120, 0 (3) ° C9 N10 C11 116.7 (3) ° N10 C11 H111 117.041 ° C11 C12 C13 118.8 (3) ° C13 C12 H121 120.783 ° C12 C13 H131 120.694 ° C9 C14 C13 118.1 (3) ° C13 C14 H141 120.983 ° N15 C16 C17 105.7 (3) ° C17 C16 C23 115.7 (3) ° C17 C16 H161 107.726 ° C16 C17 N18 120.7 (3) ° N18 C17 N21 108.0 (3) °

Br1 C2 C7 118.9 (3) ° C2 C3 C4 119.0 (3) ° C4 C3 H31 120.959 ° C3 C4 H41 119.485 ° C4 C5 C6 121.0 (3) ° C6 C5 N18 120.1 (3) ° C5 C6 C8 122.3 (3) ° C2 C7 C6 119.7 (3) ° C6 C7 H71 119.874 ° C6 C8 N15 124.4 (3) ° C8 C9 N10 116.6 (3) ° N10 C9 C14 123, 4 (3) ° N10 C11 C12 123.7 (3) ° C12 C11 H111 119.278 ° C11 C12 H121 120.443 ° C12 C13 C14 119.3 (3) ° C14 C13 H131 119.952 ° C 9 C14 H141 120.942 ° C8 N15 C16 117, 6 (3) ° N15 C16 C23 110.8 (3) ° N15 C16 H161 107.681 ° C23 C16 H161 108.910 ° C16 C17 N21 131.2 (3) ° C5 N18 C17 122.3 (3) ° 05 N18 019 128, 6 (3) ° N18 C19 020 105.7 (3) ° C20 C19 022 129.3 (3) ° C19 C20 H201 127.007 ° C17 N21 020 108.7 (3) ° C20 N21 H211 125.355 ° C19 C22 H222 109.368 ° C19 022 H223 111.184 ° H222 022 H223 107,885 ° C16 023 H231 107,712 ° C16 023 H 232 111,123 ° H231 023 H 232 110,583 ° C23 024 H241 107,661 ° C23 024 H242 109,365 ° H241 024 H242 109,671 ° C24 0 25 027 114,4 ) ° C 25 027 028 115.2 (3) ° 027 028 H282 110,269 ° 027 028 H283 108,681 ° H282 028 H283 108,963 ° 081 S80 083 115.1 (2) ° 081 S80 084 106.30 (18) ° 083 S80 084 107.0 (2) ° S80 084 089 122.1 (4) ° C84 085 086 121.6 (6) ° C86 085 H851 119.275 ° C85 086 H861 121.859 ° C86 087 088 124.9 (7) °

017 N18 019 109.0 (3) ° N18 019 022 124.9 (3) ° 019 020 N21 108.6 (3) ° N21 020 H201 124.433 ° 017 N21 H211 125.926 ° 019 022 H221 110.223 ° H221 022 H222 108.664 ° H221 022 H223 109.402 ° 016 023 024 107.9 (3) ° 024 023 H231 110.073 ° 024 023 H232 109.430 ° 023 024 025 118.8 (3) ° 025 024 H241 104.516 ° 025 024 H242 106.503 ° 024 025 026 123, 3 (3) ° 026 025 027 122.4 (3) ° 027 028 H281 108.952 ° H281 028 H282 109.738 ° H281 028 H283 110.225 ° 081 S80 082 111.9 (2) ° 082 S80 083 111.2 (3) ° 082 S80 084 104.5 (2) ° S80 084 085 117.6 (4) ° 085 084 089 120.2 (5) ° 084 085 H851 119.148 ° 085 086 087 117.5 (8) ° 087 C86 H861 120.606 ° 086 087 H871 117,763 ° C88 C87 Η871 117,376 ° C87 C88 C89 116.0 (7) ° C87 C88 Η881 122,592 ° C89 C88 Η881 121,435 ° C84 C89 C88 119.8 (8) ° C84 C89 Η891 120,080 ° C88 C89 Η891 120,078 °

Claims (32)

1. Besylate salt of a compound of formula (I): <formula> formula see original document page 80 </formula> Salt according to claim 1, which is a crystalline salt. Besylate salt according to claim 2, which is a crystalline polymorph exhibiting a powder X-ray diffraction (XRPD) pattern comprising characteristic peaks around 7.3, 7.8, 9.4 , 12.1, 14.1, 14.4, 14.7 and 15.6 degrees two theta. Besylate salt according to claim 2 or 3, which is a crystalline polymorph comprising a crystal with unit cell dimensions of a = 7,6868 A, b = 29,2607 A, c = 12,3756 A, α = 90 °, β = 97.7880 °, γ = 90 °. Besylate salt according to any one of claims 2 to 4, which is a crystalline polymorph which has a crystal structure defined by the structural coordinates as shown in the following Table. CELL 0,71073 7,687 29,261 12,376 90,000 97,788 90,000 ZERR 2 0,0001 0,0005 0,0003 0,0000 0,0008 0,0000 <table> table see original document page 81 </column> </row> <table> <table> table see original document page 82 </column> </row> <table> <table> table see original document page 83 </column> </row> <table> <table> table see original document page 84 < / column> </row> <table> <table> table see original document page 85 </column> </row> <table> <table> table see original document page 86 </column> </row> <table> <table> table see original document page 87 </column> </row> <table> <table> table see original document page 88 </column> </row> <table> <table> table see original document page 89 < / column> </row> <table> 11 [10,79029 10,50514 9,71088 11,00000 0,11566 Besylate salt according to any one of claims 2 to 5, which is a crystalline polymorph which has a crystal structure with lengths and binding angles as shown in the following Tables. Binding lengths <table> table see original document page 90 </column> </row> <table> <table> table see original document page 91 </column> </row> <table> <table> table see original document page 92 </column> </row> <table> <table> table see original document page 93 </column> </row> <table> <table> table see original document page 94 </column> </row> <table> <table> table see original document page 95 </column> </row> <table> <table> table see original document page 96 </column> </row> <table> Besylate salt according to claim 2, which is a crystalline polymorph exhibiting an XRPD pattern comprising characteristic peaks around 8.6, 10.5, 12.0, 13.1, 14. , 4 and 15.9 degrees two theta. Besylate salt according to claim 2 or 7, which is a crystalline polymorph comprising a crystal with unit cell dimensions of a = 8.92130 Á, b = 11.1536 Á, c = 25.8345 Á, α = 90 °, β = 90 °, γ = 90 °. Besylate salt according to any one of claims 2, 7 or 8, which is a crystalline polymorph which has a crystal structure defined by the structural coordinates as shown in the following Table: CELL 0.71073 8,921 11,154 25,834 90,000 90,000 90,000 ZERR 4 0,0001 0,0002 0,0004 0,0000 0,0000 0,0000 LATT -1 SYMM X + 0,500, -Y + 0,500, -Z <table> table see original document page 97 </column> < / row> <table> <table> table see original document page 98 </column> </row> <table> <table> table see original document page 99 </column> </row> <table> <table> table see original document page 100 </column> </row> <table> <table> table see original document page 101 </column> </row> <table> table see original document page 102 </column> < / row> <table> Besylate salt according to any one of claims 2 or 7 to 9, which is a crystalline polymorph which has a crystal structure having lengths and angles of attachment as shown in the following Tables. Binding lengths <table> table see original document page 102 </column> </row> <table> <table> table see original document page 103 </column> </row> <table> <table> table see original document page 104 </column> </row> <table> <table> table see original document page 105 </column> </row> <table> <table> table see original document page 106 </column> </row> <table> A besylate salt according to claim 2, which is a crystalline polymorph of a besylate salt of a compound of formula (I), which exhibits a powder X-ray diffraction (XRPD) pattern comprising caffeine peaks. characteristics around 7.6, 11.2, 12.4, 14.6, 15.2, 16.4, and 17.7 degrees two theta. The besylate salt of claim 2, which is a crystalline besylate salt polymorph of a compound of formula (I) exhibiting an XRPD pattern comprising characteristic peaks at 7.6, 10.8, 15, 2.15.9 and 22.0 degrees two theta. A pharmaceutical composition comprising a salt as defined in any one of claims 1 to 12 and a pharmaceutically acceptable carrier, excipient or diluent. Salt as defined in any one of claims 1 to 12 for use as a medicament. Use of a sedative or hypnotic amount of a salt as defined in any one of claims 1 to 12 in the manufacture of a medicament for producing sedation or hypnosis in a subject. Use of an anxiolytic amount of a salt as defined in any one of claims 1 to 12 in the manufacture of a medicament for producing anxiolysis in a subject. Use of a salt muscle relaxant amount as defined in any one of claims 1 to 12 in the manufacture of a medicament for producing muscle relaxation in a subject. Use of an anticonvulsant amount of a salt as defined in any one of claims 1 to 12 in the manufacture of a medicament for treating seizures in a subject. A process for obtaining a salt as defined in claim 1, comprising reacting a free base of a compound of formula (I) with benzene sulfonic acid. A process according to claim 19 comprising contacting the free base with benzene sulfonic acid in solution to cause a besylate salt precipitate to form. The process of claim 20 further comprising isolating the precipitate. The process according to claim 20 or 21, wherein the free base is dissolved in toluene or ethyl acetate. A process as defined in any one of claims 20 to 22, wherein benzene sulfonic acid is dissolved in ethanol. A process according to claim 20 for preparing a salt as defined in any one of claims 3 to 6 which comprises contacting a solution of a free base of a compound of formula (I) in toluene, acetate. ethyl, acetone, isopropyl acetate or ethyl formate with a solution of benzene sulfonic acid in ethanol to cause a salt precipitate to form. A process according to claim 20 for preparing a salt as defined in any one of claims 7 to 10, comprising contacting a solution of a free base of a compound of formula (I) in methanol with a solution of benzene sulfonic acid in ethanol to cause a salt precipitate to form. A process of preparing a salt as defined in claim 11, which comprises seeding, with a besylate Form 1 crystalline salt of a compound of formula (I), a solution of the filtrate separated from the precipitate formed by contacting a solution of a compound of formula (I) in ethyl acetate with a solution of benzene sulfonic acid in ethanol to produce the crystalline polymorph. A process for preparing a salt as defined in claim 12, which comprises recrystallizing a besylate Form 1 crystalline salt of a compound of formula (I) with isopropyl acetate / ethanol. A salt preparation process as defined in any one of claims 2 to 12 which comprises crystallizing a compound of formula (I) besylate from a solvent or a solvent-antisolvent or solvent mixture - cosolvent. A process for producing sedation or hypnosis in a subject comprising administering a sedative or hypnotic effective amount of a salt as defined in any one of claims 1 to 12 to the subject. A process for inducing anxiolysis in a subject comprising administering an anxiolytic effective amount of a salt as defined in any one of claims 1 to 12 to the subject. A process for inducing muscle relaxation in a subject comprising administering a muscle relaxant effective amount of a salt as defined in any one of claims 1 to 12 to the subject. A method for treating seizures in a subject comprising administering an anticonvulsant effective amount of a salt as defined in any one of claims 1 to 12 to the subject.